Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 is predominantly nuclear with regulated nucleo-cytoplasmic shuttling. Contains an N-terminal nuclear localization signal. Nuclear enrichment is well-established through multiple IDA studies (PMID:11672523, PMID:20167603, PMID:20955178). Reason: Core localization supported by phylogenetic inference and extensive experimental evidence. SIRT1 functions primarily in the nucleus for chromatin regulation and transcription factor deacetylation. Supporting Evidence: PMID:12006491 SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro. file:human/SIRT1/SIRT1-deep-research-falcon.md model: Edison Scientific Literature
GO:0003714 transcription corepressor activity	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 functions as a transcriptional corepressor through histone deacetylation and deacetylation of transcription factors. Experimentally demonstrated through IDA evidence (PMID:12535671, PMID:20955178). Reason: Core molecular function well-supported by phylogenetic inference and experimental evidence. SIRT1 mediates transcriptional repression through heterochromatin formation and deacetylation of transcription factors. Supporting Evidence: PMID:15469825 We propose a model for SirT1-mediated heterochromatin formation that includes deacetylation of histone tails, recruitment and deacetylation of histone H1, and spreading of hypomethylated H3-K79 with resultant silencing.
GO:0006974 DNA damage response	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 participates in DNA damage response through deacetylation of p53, Ku70, NBS1, and other DNA repair proteins. Well-supported by multiple experimental studies (PMID:18203716, PMID:19934257, PMID:20100829). Reason: Core biological process supported by phylogenetic inference and extensive experimental evidence. SIRT1 modulates DNA damage response through deacetylation of key repair proteins. Supporting Evidence: PMID:12006491 SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation.
GO:0031509 subtelomeric heterochromatin formation	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 promotes heterochromatin formation through histone deacetylation. Phylogenetically conserved from yeast Sir2p which is required for telomeric silencing. Reason: Core biological process supported by phylogenetic inference. SIRT1 promotes facultative heterochromatin formation through deacetylation of H4K16 and H3K9. Supporting Evidence: PMID:15469825 We propose a model for SirT1-mediated heterochromatin formation that includes deacetylation of histone tails, recruitment and deacetylation of histone H1, and spreading of hypomethylated H3-K79 with resultant silencing.
GO:0032041 histone H3K14 deacetylase activity, NAD-dependent	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 has NAD-dependent histone H3K14 deacetylase activity. Demonstrated experimentally (PMID:15469825). Reason: Core molecular function. SIRT1 deacetylates H3K14 among other histone lysines in an NAD-dependent manner. This is the primary enzymatic activity of SIRT1. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0046969 histone H3K9 deacetylase activity, NAD-dependent	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 has NAD-dependent histone H3K9 deacetylase activity. Directly demonstrated experimentally (PMID:15469825). Reason: Core molecular function. H3K9 deacetylation is a major activity of SIRT1 linked to heterochromatin formation. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0046970 histone H4K16 deacetylase activity, NAD-dependent	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 has NAD-dependent histone H4K16 deacetylase activity as its preferential histone substrate. Directly demonstrated experimentally (PMID:15469825). Reason: Core molecular function. H4K16 is the preferred histone substrate of SIRT1 and its deacetylation is critical for heterochromatin formation. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0045892 negative regulation of DNA-templated transcription	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: SIRT1 negatively regulates transcription through histone deacetylation and heterochromatin formation. Reason: Transcriptional repression is a downstream effect of chromatin modification rather than a singular core function. Supporting Evidence: PMID:15469825 Gal4-SirT1 expression resulted in the deacetylation of H4-K16 and H3-K9, recruitment of H1 within the promoter vicinity, drastically reduced reporter expression
GO:0005654 nucleoplasm	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 localizes to the nucleoplasm. Supported by multiple IDA studies and subcellular fractionation. Reason: Core localization supported by phylogenetic inference and experimental evidence. Supporting Evidence: PMID:15469825 We characterized human SirT1, one of the human homologs of the budding yeast Sir2p, an NAD+-dependent histone deacetylase involved in establishing repressive chromatin
GO:0005637 nuclear inner membrane	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 has been reported at the nuclear envelope/inner membrane (PMID:15469825). May reflect association with heterochromatin at the nuclear periphery. Reason: Localization supported by phylogenetic inference and experimental evidence. Association with nuclear envelope is consistent with heterochromatin regulation at nuclear periphery.
GO:0033553 rDNA heterochromatin	IBA GO_REF:0000033	ACCEPT	Summary: SIRT1 localizes to rDNA heterochromatin as part of the eNoSC complex that regulates rRNA transcription in response to energy status (PMID:18485871). Reason: Core localization supported by phylogenetic inference and experimental evidence. SIRT1 is a key component of the eNoSC complex at rDNA loci. Supporting Evidence: PMID:18485871 eNoSC contains Nucleomethylin, which binds histone H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1 and SUV39H1.
GO:0000781 chromosome, telomeric region	IEA GO_REF:0000108	ACCEPT	Summary: SIRT1 localizes to telomeric regions, consistent with its role in subtelomeric heterochromatin formation inherited from yeast Sir2. Reason: Localization consistent with phylogenetically conserved function in telomeric silencing.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Nuclear localization of SIRT1 is well-established through multiple experimental studies. Reason: Core localization. Duplicate of IBA annotation; IEA provides broader automated coverage.
GO:0006915 apoptotic process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT1 modulates apoptosis through deacetylation of p53 and other pro-apoptotic factors. This is a downstream consequence of its deacetylase activity. Reason: SIRT1 affects apoptosis through its primary deacetylase function on substrates like p53 and FOXO, but apoptosis regulation is not the core function of the enzyme. This is a pleiotropic effect.
GO:0007517 muscle organ development	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT1 has been implicated in muscle differentiation through deacetylation of MyoD and other myogenic factors. Reason: Downstream pleiotropic effect of SIRT1 deacetylase activity. Not the core function.
GO:0016605 PML body	IEA GO_REF:0000044	ACCEPT	Summary: SIRT1 is recruited to PML nuclear bodies upon PML overexpression where it co-localizes with p53 (PMID:12006491). Reason: Well-established localization. PML body recruitment is relevant to SIRT1 function in p53 deacetylation. Supporting Evidence: PMID:12006491 SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells
GO:0016740 transferase activity	IEA GO_REF:0000043	MODIFY	Summary: SIRT1 is classified as a transferase (EC 2.3.1.286) because the deacetylation reaction transfers the acetyl group to ADP-ribose. Reason: This is too general. SIRT1 has NAD-dependent protein deacetylase activity which is more specific. Proposed replacements: NAD-dependent protein lysine deacetylase activity
GO:0030154 cell differentiation	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: SIRT1 affects various differentiation processes through deacetylation of transcription factors. Reason: Downstream pleiotropic effect. SIRT1 impacts differentiation in multiple cell types but this is not its core function.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT1 deacetylation can promote proteasomal degradation of some substrates, including through effects on ubiquitination. Reason: Downstream effect of SIRT1 deacetylase activity on protein stability. Not the core function.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IEA GO_REF:0000120	ACCEPT	Summary: NAD-dependent protein lysine deacetylase activity is the core enzymatic function of SIRT1. Reason: Core molecular function. This is the primary enzymatic activity of SIRT1.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT1 deacetylation can affect protein stability and degradation of some substrates. Reason: Downstream effect of SIRT1 deacetylase activity. Not the core function.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: SIRT1 contains a zinc-finger motif in its catalytic domain that coordinates zinc ions for structural stability. Reason: SIRT1 contains a conserved zinc-binding domain that is essential for its structure and function.
GO:0046890 regulation of lipid biosynthetic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT1 regulates lipid metabolism through deacetylation of SREBP and other metabolic transcription factors. Reason: Downstream metabolic effect of SIRT1 deacetylase activity. Part of SIRT1 pleiotropic metabolic functions.
GO:0046970 histone H4K16 deacetylase activity, NAD-dependent	IEA GO_REF:0000117	ACCEPT	Summary: SIRT1 preferentially deacetylates H4K16 among histone substrates (PMID:15469825). Reason: Core molecular function. H4K16 is the preferred histone substrate of SIRT1.
GO:0048511 rhythmic process	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: SIRT1 can deacetylate circadian clock components BMAL1 and PER2 (PMID:18662546), but this is one of many substrates. SIRT1 core function is NAD-dependent deacetylation with broad substrate specificity including p53, NF-kB, FOXO, HIF, PGC-1alpha, and histones. Clock component deacetylation is a downstream effect of the enzymatic activity, not an evolved rhythmic function. Reason: SIRT1 has broad substrate specificity as an NAD-dependent deacetylase. While it can deacetylate clock proteins, this is one of many substrates. The core function is the NAD-dependent deacetylase activity, not rhythm generation. This represents an over-annotation based on one particular substrate class.
GO:0050793 regulation of developmental process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT1 affects various developmental processes through deacetylation of developmental transcription factors. Reason: Downstream pleiotropic effect. SIRT1 has broad effects on gene regulation but developmental regulation is not its core function.
GO:0051239 regulation of multicellular organismal process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT1 affects various organismal processes through its broad deacetylase activity. Reason: Downstream pleiotropic effect. This is too broad and vague to be informative about SIRT1 core function.
GO:0062013 positive regulation of small molecule metabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT1 regulates metabolism through deacetylation of PGC-1alpha and other metabolic regulators. Reason: Downstream metabolic effect. SIRT1 affects metabolism broadly but this is not its core function.
GO:0070403 NAD+ binding	IEA GO_REF:0000002	ACCEPT	Summary: SIRT1 binds NAD+ as an essential cofactor for its deacetylase reaction. The NAD-binding Rossmann-like fold is conserved in all sirtuins. Reason: Core molecular function. NAD+ binding is essential for SIRT1 catalytic activity.
GO:0071456 cellular response to hypoxia	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: SIRT1 deacetylates HIF1alpha and HIF2alpha to modulate hypoxia responses. Reason: Downstream effect through deacetylation of HIF transcription factors. One of many substrates of SIRT1.
GO:0141208 NAD-dependent protein lysine delactylase activity	IEA GO_REF:0000116	ACCEPT	Summary: SIRT1 may have delactylase activity in addition to its primary deacetylase function. IDA evidence from PMID:38512451. Reason: Molecular function consistent with the broad deacylase activity of sirtuins.
GO:0160011 NAD-dependent protein decrotonylase activity	IEA GO_REF:0000116	ACCEPT	Summary: SIRT1 has decrotonylase activity in addition to deacetylase activity. IDA evidence from PMID:28497810. Reason: Molecular function consistent with the broad deacylase activity of sirtuins. SIRT1 can remove various acyl modifications.
GO:0005515 protein binding	IPI PMID:11672523 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.	REMOVE	Summary: SIRT1 binds p53 (PMID:11672523). This protein binding annotation is uninformative - the specific interaction with p53 is better captured by the p53 binding annotation (GO:0002039). Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions (e.g. p53 binding, transcription factor binding). Supporting Evidence: PMID:11672523 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.
GO:0005515 protein binding	IPI PMID:12006491 Human SIR2 deacetylates p53 and antagonizes PML/p53-induced ...	REMOVE	Summary: SIRT1 binds PML and p53 at PML nuclear bodies (PMID:12006491). Generic protein binding is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:12006491 Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence.
GO:0005515 protein binding	IPI PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression.
GO:0005515 protein binding	IPI PMID:14976264 Stress-dependent regulation of FOXO transcription factors by...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:14976264 Feb 19. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.
GO:0005515 protein binding	IPI PMID:15126506 FOXO4 is acetylated upon peroxide stress and deacetylated by...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:15126506 2004 May 4. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).
GO:0005515 protein binding	IPI PMID:15152190 Modulation of NF-kappaB-dependent transcription and cell sur...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:15152190 May 20. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.
GO:0005515 protein binding	IPI PMID:15175761 Sirt1 promotes fat mobilization in white adipocytes by repre...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:15175761 Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.
GO:0005515 protein binding	IPI PMID:15205477 Calorie restriction promotes mammalian cell survival by indu...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:15205477 Jun 17. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.
GO:0005515 protein binding	IPI PMID:15220471 Silent information regulator 2 potentiates Foxo1-mediated tr...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:15220471 Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.
GO:0005515 protein binding	IPI PMID:15632193 SIRT1 deacetylation and repression of p300 involves lysine r...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:15632193 2005 Jan 4. SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1.
GO:0005515 protein binding	IPI PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation.
GO:0005515 protein binding	IPI PMID:16892051 Interactions between E2F1 and SirT1 regulate apoptotic respo...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:16892051 Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage.
GO:0005515 protein binding	IPI PMID:16998810 SIRT1 interacts with p73 and suppresses p73-dependent transc...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:16998810 SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity.
GO:0005515 protein binding	IPI PMID:17334224 SIRT1 promotes DNA repair activity and deacetylation of Ku70...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:17334224 SIRT1 promotes DNA repair activity and deacetylation of Ku70.
GO:0005515 protein binding	IPI PMID:17612497 SIRT1 regulates the function of the Nijmegen breakage syndro...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:17612497 SIRT1 regulates the function of the Nijmegen breakage syndrome protein.
GO:0005515 protein binding	IPI PMID:17680780 Sirt1 interacts with transducin-like enhancer of split-1 to ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:17680780 Sirt1 interacts with transducin-like enhancer of split-1 to inhibit nuclear factor kappaB-mediated transcription.
GO:0005515 protein binding	IPI PMID:17901049 The direct involvement of SirT1 in insulin-induced insulin r...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:17901049 2007 Sep 27. The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation.
GO:0005515 protein binding	IPI PMID:17936707 SIRT1 deacetylates and positively regulates the nuclear rece...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:17936707 SIRT1 deacetylates and positively regulates the nuclear receptor LXR.
GO:0005515 protein binding	IPI PMID:17964266 Active regulator of SIRT1 cooperates with SIRT1 and facilita...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:17964266 Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity.
GO:0005515 protein binding	IPI PMID:18004385 SIRT1 regulates the histone methyl-transferase SUV39H1 durin...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:18004385 SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation.
GO:0005515 protein binding	IPI PMID:18203716 Regulation of WRN protein cellular localization and enzymati...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:18203716 2008 Jan 17. Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation.
GO:0005515 protein binding	IPI PMID:18235501 DBC1 is a negative regulator of SIRT1.	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:18235501 DBC1 is a negative regulator of SIRT1.
GO:0005515 protein binding	IPI PMID:18235502 Negative regulation of the deacetylase SIRT1 by DBC1.	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:18235502 Negative regulation of the deacetylase SIRT1 by DBC1.
GO:0005515 protein binding	IPI PMID:18296641 A role for the NAD-dependent deacetylase Sirt1 in the regula...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:18296641 A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy.
GO:0005515 protein binding	IPI PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:18485871 Epigenetic control of rDNA loci in response to intracellular energy status.
GO:0005515 protein binding	IPI PMID:19047049 Hyaluronan-mediated CD44 interaction with p300 and SIRT1 reg...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19047049 2008 Dec 1. Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells.
GO:0005515 protein binding	IPI PMID:19188449 hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic p...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19188449 Feb 2. hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in response to DNA damage.
GO:0005515 protein binding	IPI PMID:19236849 Carboxy-terminal phosphorylation of SIRT1 by protein kinase ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19236849 Carboxy-terminal phosphorylation of SIRT1 by protein kinase CK2.
GO:0005515 protein binding	IPI PMID:19343720 Identification and characterization of proteins interacting ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19343720 Identification and characterization of proteins interacting with SIRT1 and SIRT3: implications in the anti-aging and metabolic effects of sirtuins.
GO:0005515 protein binding	IPI PMID:19478080 Enzymes in the NAD+ salvage pathway regulate SIRT1 activity ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19478080 2009 May 28. Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters.
GO:0005515 protein binding	IPI PMID:19680552 CK2 is the regulator of SIRT1 substrate-binding affinity, de...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19680552 CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA-damage.
GO:0005515 protein binding	IPI PMID:19690166 Transcriptional corepressor SMILE recruits SIRT1 to inhibit ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19690166 2009 Aug 18. Transcriptional corepressor SMILE recruits SIRT1 to inhibit nuclear receptor estrogen receptor-related receptor gamma transactivation.
GO:0005515 protein binding	IPI PMID:19934257 SIRT1 deacetylates APE1 and regulates cellular base excision...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19934257 Nov 24. SIRT1 deacetylates APE1 and regulates cellular base excision repair.
GO:0005515 protein binding	IPI PMID:19934264 Reciprocal roles of SIRT1 and SKIP in the regulation of RAR ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:19934264 Nov 24. Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells.
GO:0005515 protein binding	IPI PMID:20169165 SIRT1 negatively regulates the mammalian target of rapamycin...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:20169165 SIRT1 negatively regulates the mammalian target of rapamycin.
GO:0005515 protein binding	IPI PMID:20375098 Transcriptional corepressor SHP recruits SIRT1 histone deace...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:20375098 Apr 7. Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation.
GO:0005515 protein binding	IPI PMID:20439735 SIRT1 regulates Dishevelled proteins and promotes transient ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:20439735 SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling.
GO:0005515 protein binding	IPI PMID:20660480 SIRT1 is regulated by a PPAR{γ}-SIRT1 negative feedback loop...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:20660480 Jul 25. SIRT1 is regulated by a PPAR{γ}-SIRT1 negative feedback loop associated with senescence.
GO:0005515 protein binding	IPI PMID:20670893 SIRT1 regulates UV-induced DNA repair through deacetylating ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:20670893 SIRT1 regulates UV-induced DNA repair through deacetylating XPA.
GO:0005515 protein binding	IPI PMID:20817729 SIRT1 deacetylates and inhibits SREBP-1C activity in regulat...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:20817729 2010 Sep 3. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism.
GO:0005515 protein binding	IPI PMID:21081649 SIRT2 regulates NF-κB dependent gene expression through deac...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21081649 Nov 16. SIRT2 regulates NF-κB dependent gene expression through deacetylation of p65 Lys310.
GO:0005515 protein binding	IPI PMID:21241768 Phosphoinositide 3-kinase as a novel functional target for t...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21241768 Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1.
GO:0005515 protein binding	IPI PMID:21245319 Methyltransferase Set7/9 regulates p53 activity by interacti...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21245319 Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1).
GO:0005515 protein binding	IPI PMID:21471201 Cancer cell survival following DNA damage-mediated premature...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21471201 2011 Apr 6. Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1.
GO:0005515 protein binding	IPI PMID:21555002 EVI1 up-regulates the stress responsive gene SIRT1 which tri...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21555002 EVI1 up-regulates the stress responsive gene SIRT1 which triggers deacetylation and degradation of EVI1.
GO:0005515 protein binding	IPI PMID:21698133 SIRT1 promotes N-Myc oncogenesis through a positive feedback...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21698133 2011 Jun 16. SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.
GO:0005515 protein binding	IPI PMID:21775285 The deacetylase SIRT1 promotes membrane localization and act...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21775285 The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.
GO:0005515 protein binding	IPI PMID:21807113 Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21807113 Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.
GO:0005515 protein binding	IPI PMID:21890893 SIRT1 links CIITA deacetylation to MHC II activation.	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21890893 Sep 2. SIRT1 links CIITA deacetylation to MHC II activation.
GO:0005515 protein binding	IPI PMID:21909281 The evolutionarily conserved longevity determinants HCF-1 an...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21909281 2011 Sep 1. The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.
GO:0005515 protein binding	IPI PMID:21947282 SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) prote...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21947282 Sep 26. SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.
GO:0005515 protein binding	IPI PMID:21968188 p53 deacetylation by SIRT1 decreases during protein kinase C...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21968188 2011 Sep 29. p53 deacetylation by SIRT1 decreases during protein kinase CKII downregulation-mediated cellular senescence.
GO:0005515 protein binding	IPI PMID:22094255 Oxidative damage targets complexes containing DNA methyltran...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:22094255 Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands.
GO:0005515 protein binding	IPI PMID:22169038 SIRT1 activates MAO-A in the brain to mediate anxiety and ex...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:22169038 Dec 8. SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive.
GO:0005515 protein binding	IPI PMID:22190034 Global landscape of HIV-human protein complexes.	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:22190034 Global landscape of HIV-human protein complexes.
GO:0005515 protein binding	IPI PMID:22510882 Novel repressor regulates insulin sensitivity through intera...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:22510882 Novel repressor regulates insulin sensitivity through interaction with Foxo1.
GO:0005515 protein binding	IPI PMID:22863012 Brown remodeling of white adipose tissue by SirT1-dependent ...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:22863012 Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ.
GO:0005515 protein binding	IPI PMID:24681097 AROS has a context-dependent effect on SIRT1.	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:24681097 2014 Mar 26. AROS has a context-dependent effect on SIRT1.
GO:0005515 protein binding	IPI PMID:25751424 NAD(+)-SIRT1 control of H3K4 trimethylation through circadia...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:25751424 Mar 9. NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:31403225 The interactome of KRAB zinc finger proteins reveals the evo...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:31403225 Aug 12. The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification.
GO:0005515 protein binding	IPI PMID:32761762 CSAG2 is a cancer-specific activator of SIRT1.	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:32761762 CSAG2 is a cancer-specific activator of SIRT1.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 represses RNA Pol II transcription through histone deacetylation and deacetylation of transcription factors. Reason: Represents downstream transcriptional regulation rather than a singular core function. Supporting Evidence: PMID:15469825 Gal4-SirT1 expression resulted in the deacetylation of H4-K16 and H3-K9, recruitment of H1 within the promoter vicinity, drastically reduced reporter expression
GO:0000720 pyrimidine dimer repair by nucleotide-excision repair	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 participates in DNA repair processes through deacetylation of repair proteins. This is one of many DNA damage response roles mediated by SIRT1 deacetylase activity. Reason: Downstream effect of SIRT1 deacetylase activity on DNA repair proteins. SIRT1 contributes to DNA repair but this specific pathway is not its core function.
GO:0000731 DNA synthesis involved in DNA repair	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 participates in DNA repair processes through deacetylation of repair proteins. This is one of many DNA damage response roles mediated by SIRT1 deacetylase activity. Reason: Downstream effect of SIRT1 deacetylase activity on DNA repair proteins. SIRT1 contributes to DNA repair but this specific pathway is not its core function.
GO:0000785 chromatin	IEA GO_REF:0000107	ACCEPT	Summary: SIRT1 localizes to chromatin where it functions as a histone deacetylase. Core localization consistent with its primary enzymatic function. Reason: Core localization. SIRT1 functions at chromatin to deacetylate histones and regulate transcription. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0000792 heterochromatin	IEA GO_REF:0000107	ACCEPT	Summary: SIRT1 promotes heterochromatin formation through histone deacetylation. Core localization consistent with its primary function in chromatin silencing. Reason: Core localization. SIRT1 promotes facultative heterochromatin formation through deacetylation of H4K16 and H3K9. Supporting Evidence: PMID:15469825 We propose a model for SirT1-mediated heterochromatin formation that includes deacetylation of histone tails, recruitment and deacetylation of histone H1, and spreading of hypomethylated H3-K79 with resultant silencing.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA GO_REF:0000107	REMOVE	Summary: SIRT1 does not have intrinsic sequence-specific DNA binding activity. It is recruited to promoters through interactions with transcription factors rather than direct DNA sequence recognition. Reason: SIRT1 lacks intrinsic sequence-specific DNA binding. It is a deacetylase that is recruited to chromatin through protein-protein interactions, not DNA sequence recognition.
GO:0001525 angiogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 affects angiogenesis through deacetylation of HIF and FOXO transcription factors. This is a downstream pleiotropic effect of its broad deacetylase activity. Reason: Downstream pleiotropic effect. SIRT1 modulates angiogenesis through its effects on transcription factors but this is not its core function.
GO:0001678 intracellular glucose homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates glucose homeostasis through deacetylation of PGC-1alpha, FOXO factors, and other metabolic regulators. NAD+ dependence links SIRT1 activity to metabolic state. Reason: Important downstream metabolic effect of SIRT1 deacetylase activity. SIRT1 functions as a metabolic sensor through NAD+ dependence but glucose homeostasis per se is not its core function.
GO:0002039 p53 binding	IEA GO_REF:0000107	ACCEPT	Summary: SIRT1 directly binds p53 and deacetylates its C-terminal K382 residue. Well-established substrate interaction demonstrated in multiple studies (PMID:11672523, PMID:12006491). Reason: Core substrate interaction. p53 is a major non-histone substrate of SIRT1. Binding is required for deacetylation of p53 K382. Supporting Evidence: PMID:11672523 the protein product of the gene hSIR2(SIRT1), the human homolog of the S. cerevisiae Sir2 protein known to be involved in cell aging and in the response to DNA damage, binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue PMID:12006491 SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation.
GO:0003713 transcription coactivator activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 is primarily a transcriptional corepressor through histone deacetylation. However, in some contexts deacetylation of specific transcription factors can enhance their activity. This is a minor function compared to corepressor activity. Reason: Context-dependent function. SIRT1 is predominantly a corepressor but can have coactivator effects in specific contexts. Not the core function.
GO:0003714 transcription corepressor activity	IEA GO_REF:0000107	ACCEPT	Summary: SIRT1 functions as a transcriptional corepressor through histone deacetylation and deacetylation of transcription factors. Core molecular function well-supported by phylogenetic inference and experimental evidence (PMID:15469825, PMID:20955178). Reason: Core molecular function. SIRT1 mediates transcriptional repression through heterochromatin formation and deacetylation of transcription factors. Supporting Evidence: PMID:15469825 We propose a model for SirT1-mediated heterochromatin formation that includes deacetylation of histone tails, recruitment and deacetylation of histone H1, and spreading of hypomethylated H3-K79 with resultant silencing.
GO:0004857 enzyme inhibitor activity	IEA GO_REF:0000107	REMOVE	Summary: SIRT1 is an enzyme (deacetylase) itself, not primarily an enzyme inhibitor. While deacetylation can modulate enzyme activity, this is an indirect effect. This annotation is misleading. Reason: Misleading annotation. SIRT1 is a deacetylase enzyme, not an enzyme inhibitor. Any effects on other enzyme activities are indirect consequences of its deacetylation activity.
GO:0006642 triglyceride mobilization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates lipid metabolism through deacetylation of SREBP and other lipid metabolism transcription factors. This is a downstream pleiotropic effect. Reason: Downstream metabolic effect. SIRT1 modulates lipid metabolism through transcription factor deacetylation but this is not its core function.
GO:0007623 circadian rhythm	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: SIRT1 can deacetylate circadian clock components but this is one of many substrates. Clock regulation is not the core function. Reason: SIRT1 deacetylates many transcription factors including clock proteins. This represents an over-annotation based on one substrate class rather than the core NAD-dependent deacetylase function.
GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 modulates DNA damage-induced apoptosis primarily through deacetylation of p53, suppressing its pro-apoptotic activity (PMID:11672523). This is a downstream effect of SIRT1 deacetylase activity. Reason: Downstream effect of SIRT1 deacetylase activity on p53 and other apoptotic regulators. Apoptosis regulation is not SIRT1's core function. Supporting Evidence: PMID:11672523 Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53. In contrast, expression of a catalytically inactive hSir2 protein potentiates p53-dependent apoptosis and radiosensitivity.
GO:0009267 cellular response to starvation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 is activated by increased NAD+/NADH ratio during starvation and mediates metabolic adaptations through deacetylation of PGC-1alpha, FOXO, and other metabolic regulators (PMID:18485871). This is an important metabolic sensor function. Reason: Downstream metabolic response. SIRT1 NAD+ dependence makes it a metabolic sensor but starvation response per se is not its core function. Supporting Evidence: PMID:18485871 a change in the NAD(+)/NADH ratio induced by reduction of energy status could activate SIRT1, leading to deacetylation of histone H3 and dimethylation at Lys9 by SUV39H1, thus establishing silent chromatin
GO:0010875 positive regulation of cholesterol efflux	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates cholesterol metabolism through deacetylation of LXR and other cholesterol metabolism regulators. This is a downstream pleiotropic metabolic effect. Reason: Downstream metabolic effect. SIRT1 modulates cholesterol metabolism through transcription factor deacetylation but this is not its core function.
GO:0010883 regulation of lipid storage	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates lipid storage through deacetylation of SREBP and other lipid metabolism transcription factors. This is a downstream pleiotropic metabolic effect. Reason: Downstream metabolic effect. SIRT1 modulates lipid storage through transcription factor deacetylation but this is not its core function.
GO:0010906 regulation of glucose metabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates glucose metabolism through deacetylation of PGC-1alpha, FOXO factors, and other metabolic regulators. NAD+ dependence links SIRT1 activity to metabolic state. Reason: Important downstream metabolic effect of SIRT1 deacetylase activity but glucose metabolism per se is not its core function.
GO:0016239 positive regulation of macroautophagy	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates autophagy through deacetylation of autophagy-related proteins and FOXO transcription factors. This is a downstream effect of SIRT1 deacetylase activity. Reason: Downstream effect. SIRT1 modulates autophagy through protein deacetylation but autophagy regulation is not its core function.
GO:0017136 histone deacetylase activity, NAD-dependent	IEA GO_REF:0000107	ACCEPT	Summary: NAD-dependent histone deacetylase activity is the core enzymatic function of SIRT1. Well-demonstrated through multiple experimental studies (PMID:15469825, PMID:12006491). Reason: Core molecular function. This is the primary enzymatic activity of SIRT1 on histones. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0019213 deacetylase activity	IEA GO_REF:0000107	ACCEPT	Summary: Deacetylase activity is the core enzymatic function of SIRT1. This is a broader parent term; more specific NAD-dependent protein lysine deacetylase activity annotations are preferred. Reason: Core molecular function. SIRT1 is an NAD-dependent deacetylase. This general term is correct but less informative than more specific deacetylase annotations.
GO:0019899 enzyme binding	IEA GO_REF:0000107	ACCEPT	Summary: SIRT1 binds multiple enzymes and enzyme complexes. Reason: Enzyme binding is supported by multiple interaction studies.
GO:0019904 protein domain specific binding	IEA GO_REF:0000107	REMOVE	Summary: SIRT1 interacts with specific protein domains but this generic annotation is not informative about the specific interactions. Reason: Generic protein domain binding annotation is uninformative. More specific annotations for particular domain interactions are preferred.
GO:0030225 macrophage differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 affects macrophage differentiation through deacetylation of transcription factors. This is a downstream pleiotropic effect. Reason: Downstream pleiotropic effect on immune cell differentiation. Not the core function of SIRT1.
GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can modulate TGF-beta signaling through deacetylation of SMAD proteins. This is a downstream pleiotropic effect. Reason: Downstream signaling effect through transcription factor deacetylation. Not the core function of SIRT1.
GO:0030968 endoplasmic reticulum unfolded protein response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 deacetylates XBP1s and modulates the UPR (PMID:20955178). This is a downstream effect of SIRT1 deacetylase activity. Reason: Downstream effect through XBP1s deacetylation. UPR regulation is not the core function of SIRT1. Supporting Evidence: PMID:20955178 SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.
GO:0031393 negative regulation of prostaglandin biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can affect prostaglandin biosynthesis through deacetylation of inflammatory regulators like NF-kB. This is a downstream pleiotropic effect. Reason: Downstream anti-inflammatory effect through transcription factor deacetylation. Not the core function of SIRT1.
GO:0031648 protein destabilization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 deacetylation can promote protein destabilization and degradation of some substrates (e.g., PER2). This is a downstream effect of deacetylase activity. Reason: Downstream effect on specific substrates. Protein destabilization per se is not SIRT1's core function.
GO:0032007 negative regulation of TOR signaling	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can modulate mTOR signaling through deacetylation of pathway components. This is a downstream metabolic signaling effect. Reason: Downstream signaling effect. mTOR regulation is not the core function of SIRT1.
GO:0032868 response to insulin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 modulates insulin sensitivity through deacetylation of IRS proteins and insulin signaling components. Downstream metabolic effect. Reason: Downstream metabolic effect. Insulin response is not the core function of SIRT1.
GO:0032922 circadian regulation of gene expression	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 modulates circadian clock components through deacetylation. Reason: Circadian regulation is a downstream outcome of SIRT1 activity.
GO:0032991 protein-containing complex	IEA GO_REF:0000107	ACCEPT	Summary: SIRT1 functions in various protein complexes including the eNoSC complex at rDNA loci (PMID:18485871). This is a generic localization annotation. Reason: SIRT1 functions within protein complexes. This generic annotation is consistent with its participation in eNoSC and other chromatin regulatory complexes.
GO:0033210 leptin-mediated signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can modulate leptin signaling in the hypothalamus. This is a downstream metabolic signaling effect. Reason: Downstream signaling effect in specific tissues. Leptin signaling is not the core function of SIRT1.
GO:0033558 protein lysine deacetylase activity	IEA GO_REF:0000107	ACCEPT	Summary: Protein lysine deacetylase activity is the core enzymatic function of SIRT1. SIRT1 deacetylates histones and many non-histone proteins at lysine residues (PMID:15469825, PMID:11672523). Reason: Core molecular function. This is the primary enzymatic activity of SIRT1. Supporting Evidence: PMID:11672523 the protein product of the gene hSIR2(SIRT1)...binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue
GO:0034391 regulation of smooth muscle cell apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can modulate smooth muscle cell apoptosis through deacetylation of p53 and other apoptotic regulators. This is a downstream pleiotropic effect in specific cell types. Reason: Downstream cell type-specific effect. Smooth muscle cell apoptosis regulation is not the core function of SIRT1.
GO:0035356 intracellular triglyceride homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates triglyceride metabolism through deacetylation of SREBP and other metabolic transcription factors. Downstream metabolic effect. Reason: Downstream metabolic effect. Triglyceride homeostasis is not the core function of SIRT1.
GO:0035358 regulation of peroxisome proliferator activated receptor signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can modulate PPAR signaling through deacetylation of PPAR coactivators like PGC-1alpha. Downstream metabolic signaling effect. Reason: Downstream metabolic signaling effect. PPAR signaling regulation is not the core function of SIRT1.
GO:0042632 cholesterol homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates cholesterol metabolism through deacetylation of LXR and other cholesterol metabolism regulators. Downstream metabolic effect. Reason: Downstream metabolic effect. Cholesterol homeostasis is not the core function of SIRT1.
GO:0043065 positive regulation of apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 generally suppresses apoptosis through p53 deacetylation but can have context-dependent pro-apoptotic effects. Downstream effect. Reason: Downstream context-dependent effect on apoptosis. Apoptosis regulation is not the core function of SIRT1.
GO:0044321 response to leptin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can modulate leptin signaling in the hypothalamus. Downstream metabolic signaling effect. Reason: Downstream metabolic signaling effect. Leptin response is not the core function of SIRT1.
GO:0045599 negative regulation of fat cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 inhibits adipogenesis through deacetylation of PPAR-gamma and other adipogenic transcription factors. Downstream metabolic effect. Reason: Downstream metabolic effect on adipocyte differentiation. Not the core function of SIRT1.
GO:0045722 positive regulation of gluconeogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 promotes gluconeogenesis through deacetylation and activation of PGC-1alpha and FOXO1. Well-supported metabolic function. Reason: Important downstream metabolic effect through PGC-1alpha/FOXO1 deacetylation. Not the core function but a well-established metabolic role.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 is predominantly a transcriptional corepressor but can positively regulate transcription of some genes through effects on specific transcription factors. Context-dependent effect. Reason: Secondary function. SIRT1 is primarily a corepressor but has context-dependent coactivator effects on some promoters.
GO:0046969 histone H3K9 deacetylase activity, NAD-dependent	IEA GO_REF:0000107	ACCEPT	Summary: H3K9 deacetylation is a core histone modification activity of SIRT1. Well-demonstrated in PMID:15469825. Reason: Core molecular function. H3K9 deacetylation is one of SIRT1's primary histone substrate specificities. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0050872 white fat cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 inhibits white adipocyte differentiation through effects on PPAR-gamma and other adipogenic regulators. Downstream metabolic effect. Reason: Downstream metabolic effect on adipocyte differentiation. Not the core function of SIRT1.
GO:0051152 positive regulation of smooth muscle cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 affects smooth muscle cell differentiation through transcription factor deacetylation. Downstream pleiotropic effect. Reason: Downstream cell type-specific effect. Not the core function of SIRT1.
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can modulate PI3K/AKT signaling through effects on insulin signaling and other pathways. Downstream signaling effect. Reason: Downstream signaling effect. PI3K/AKT regulation is not the core function of SIRT1.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can negatively modulate PI3K/AKT signaling in some contexts. Context-dependent downstream signaling effect. Reason: Downstream context-dependent signaling effect. PI3K/AKT regulation is not the core function of SIRT1.
GO:0055089 fatty acid homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates fatty acid metabolism through deacetylation of SREBP and other lipid metabolism transcription factors. Downstream metabolic effect. Reason: Downstream metabolic effect. Fatty acid homeostasis is not the core function of SIRT1.
GO:0060907 positive regulation of macrophage cytokine production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 modulates macrophage cytokine production through NF-kB deacetylation and other inflammatory regulators. Downstream immune effect. Reason: Downstream immune/inflammatory effect. Macrophage cytokine regulation is not the core function of SIRT1.
GO:0070857 regulation of bile acid biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 regulates bile acid metabolism through deacetylation of FXR and other bile acid metabolism regulators. Downstream metabolic effect. Reason: Downstream metabolic effect. Bile acid regulation is not the core function of SIRT1.
GO:0071479 cellular response to ionizing radiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 modulates DNA damage response through deacetylation of p53 and other DNA repair/checkpoint proteins. Downstream stress response effect. Reason: Downstream stress response effect through p53 and DNA repair protein deacetylation. Not the core function of SIRT1.
GO:0090335 regulation of brown fat cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 affects brown adipocyte differentiation through effects on PGC-1alpha and other thermogenic regulators. Downstream metabolic effect. Reason: Downstream metabolic effect on adipocyte differentiation. Not the core function of SIRT1.
GO:0106231 NAD-dependent protein-lysine depropionylase activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: SIRT1 can remove propionyl groups from lysine residues in addition to acetyl groups. Minor enzymatic activity compared to deacetylation. Reason: Secondary enzymatic activity. Depropionylation is a minor activity compared to the primary deacetylase function.
GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 suppresses p53-mediated apoptosis through deacetylation of p53 K382 (PMID:11672523). Well-established downstream effect. Reason: Downstream effect of SIRT1 deacetylase activity on p53. Apoptosis regulation is not SIRT1's core function but this is a well-supported effect. Supporting Evidence: PMID:11672523 Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53. In contrast, expression of a catalytically inactive hSir2 protein potentiates p53-dependent apoptosis and radiosensitivity.
GO:1902237 positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 can modulate ER stress-induced apoptosis through effects on XBP1s and other UPR regulators (PMID:20955178). Context-dependent effect. Reason: Downstream context-dependent effect on ER stress apoptosis. Not the core function of SIRT1. Supporting Evidence: PMID:20955178 Sirt1-/- MEFs display a greater resistance to ER-stress-induced apoptotic cell death compared with Sirt1+/+ MEFs.
GO:1904179 positive regulation of adipose tissue development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SIRT1 affects adipose tissue development through effects on PPAR-gamma and other adipogenic regulators. Context-dependent downstream metabolic effect. Reason: Downstream metabolic effect on adipose development. Not the core function of SIRT1.
GO:1990841 promoter-specific chromatin binding	IEA GO_REF:0000107	ACCEPT	Summary: SIRT1 is recruited to specific promoters through interactions with transcription factors. Core localization related to its transcriptional regulatory function. Reason: Core localization. SIRT1 binds chromatin at specific promoters to regulate transcription through histone deacetylation.
GO:2000111 positive regulation of macrophage apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Annotation indicates SIRT1 can influence macrophage apoptosis through deacetylation of regulatory factors in immune contexts. Reason: Downstream immune regulation rather than a core function; keep as non-core despite indirect support.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: SIRT1 localizes to nuclear compartments including the nucleoplasm. Reason: Consistent with nuclear localization shown in immunostaining studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005739 mitochondrion	IDA GO_REF:0000052	UNDECIDED	Summary: Mitochondrial localization for full-length SIRT1 is not clearly supported here. Reason: Evidence may be context- or isoform-specific; requires confirmation. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: SIRT1 localizes to the cytosol as well as the nucleus. Reason: Immunostaining shows cytoplasmic localization. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0000183 rDNA heterochromatin formation	TAS Reactome:R-HSA-427359	ACCEPT	Summary: SIRT1 in eNoSC promotes rRNA gene silencing via histone modification. Reason: Reactome summary describes eNoSC-mediated repression of rRNA genes. Supporting Evidence: Reactome:R-HSA-427359 Deacetylation and methylation of histone H3 in the chromatin of a rRNA gene by eNoSC causes reduced expression of the gene. Reactome:R-HSA-427359 eNoSC comprises Nucleomethylin (NML), SIRT1, and the histone methylase SUV39H1 (Murayama et al. 2008).
GO:1900034 regulation of cellular response to heat	TAS Reactome:R-HSA-3371453	KEEP AS NON CORE	Summary: SIRT1 participates in heat shock response regulation via HSF1 deacetylation. Reason: Pathway-level regulatory effect rather than core function. Supporting Evidence: Reactome:R-HSA-3371467 Sirtuin 1 (SIRT1) functions as a NAD(+)-dependent deacetylase, which regulates the heat shock response through deacetylation of HSF1 at Lys80.
GO:0034979 NAD-dependent protein lysine deacetylase activity	TAS Reactome:R-HSA-3371467	ACCEPT	Summary: SIRT1 functions as a NAD-dependent deacetylase in the HSF1 heat shock pathway. Reason: Core enzymatic activity supported in Reactome summary. Supporting Evidence: Reactome:R-HSA-3371467 Sirtuin 1 (SIRT1) functions as a NAD(+)-dependent deacetylase, which regulates the heat shock response through deacetylation of HSF1 at Lys80.
GO:0034979 NAD-dependent protein lysine deacetylase activity	TAS Reactome:R-HSA-9620532	ACCEPT	Summary: SIRT1 deacetylates FOXO3 as an NAD-dependent histone deacetylase. Reason: Reactome summary documents FOXO3 deacetylation by SIRT1. Supporting Evidence: Reactome:R-HSA-9620532 SIRT1, an NAD-dependent histone deacetylase, deacetylates FOXO3.
GO:0000183 rDNA heterochromatin formation	IMP PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	ACCEPT	Summary: eNoSC containing SIRT1 establishes silent chromatin at rDNA loci. Reason: Supported by the eNoSC complex and rDNA chromatin silencing. Supporting Evidence: PMID:18485871 eNoSC contains Nucleomethylin, which binds histone H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1 and SUV39H1. PMID:18485871 thus establishing silent chromatin in the rDNA locus.
GO:0005730 nucleolus	IDA PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	KEEP AS NON CORE	Summary: SIRT1 participates in rDNA locus regulation within the nucleolar context. Reason: Context-specific localization associated with rDNA regulation. Supporting Evidence: PMID:18485871 eNoSC contains Nucleomethylin, which binds histone H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1 and SUV39H1.
GO:0042149 cellular response to glucose starvation	IMP PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	MARK AS OVER ANNOTATED	Summary: This study links energy status to rRNA transcription, but glucose-specific starvation is not explicit. Reason: The term is too specific relative to the evidence presented. Supporting Evidence: PMID:18485871 Furthermore, eNoSC promotes restoration of energy balance by limiting rRNA transcription, thus protecting cells from energy deprivation-dependent apoptosis.
GO:0045786 negative regulation of cell cycle	IMP PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	UNDECIDED	Summary: Negative regulation of cell cycle is not described in the PMID:18485871 abstract. Reason: Insufficient evidence in this reference for cell cycle regulation. Supporting Evidence: PMID:18485871 SIRT1 and SUV39H1 are required for energy-dependent transcriptional repression
GO:0045892 negative regulation of DNA-templated transcription	IMP PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	KEEP AS NON CORE	Summary: SIRT1 and SUV39H1 are required for energy-dependent transcriptional repression at rDNA loci. Reason: Represents context-specific repression of rRNA transcription. Supporting Evidence: PMID:18485871 SIRT1 and SUV39H1 are required for energy-dependent transcriptional repression
GO:0046015 regulation of transcription by glucose	IMP PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	MARK AS OVER ANNOTATED	Summary: The evidence discusses energy status broadly rather than glucose-specific transcriptional control. Reason: Glucose-specific regulation is not explicit in the abstract. Supporting Evidence: PMID:18485871 Furthermore, eNoSC promotes restoration of energy balance by limiting rRNA transcription, thus protecting cells from energy deprivation-dependent apoptosis.
GO:0097009 energy homeostasis	IMP PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	KEEP AS NON CORE	Summary: eNoSC limits rRNA transcription to restore energy balance. Reason: Energy homeostasis is a downstream consequence of rDNA repression. Supporting Evidence: PMID:18485871 Furthermore, eNoSC promotes restoration of energy balance by limiting rRNA transcription, thus protecting cells from energy deprivation-dependent apoptosis.
GO:0003714 transcription corepressor activity	IDA PMID:20955178 Regulation of unfolded protein response modulator XBP1s by a...	ACCEPT	Summary: SIRT1 represses XBP1s transcriptional activity via deacetylation. Reason: Corepressor activity is supported by inhibition of XBP1s. Supporting Evidence: PMID:20955178 SIRT1 deacetylates XBP1s and inhibits its transcriptional activity
GO:0030968 endoplasmic reticulum unfolded protein response	IDA PMID:20955178 Regulation of unfolded protein response modulator XBP1s by a...	KEEP AS NON CORE	Summary: SIRT1 modulates the unfolded protein response through XBP1s deacetylation. Reason: Represents a pathway-specific regulatory role. Supporting Evidence: PMID:20955178 Deficiency of SIRT1 enhances XBP1s-mediated luciferase reporter activity in HEK (human embryonic kidney)-293 cells
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:20955178 Regulation of unfolded protein response modulator XBP1s by a...	ACCEPT	Summary: SIRT1 deacetylates XBP1s as a lysine deacetylase. Reason: Direct deacetylation of XBP1s supports this activity. Supporting Evidence: PMID:20955178 In the present study, we demonstrate that XBP1s is a target of acetylation and deacetylation mediated by p300 and SIRT1 (sirtuin 1) respectively
GO:0004407 histone deacetylase activity	EXP PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	ACCEPT	Summary: SIRT1 contributes to histone deacetylation during rDNA silencing. Reason: Core enzymatic activity within the eNoSC complex. Supporting Evidence: PMID:18485871 SIRT1 and SUV39H1 are required for energy-dependent transcriptional repression
GO:0033558 protein lysine deacetylase activity	TAS Reactome:R-HSA-9825772	ACCEPT	Summary: SIRT1 deacetylates HINT1, consistent with protein lysine deacetylase activity. Reason: Reactome summary documents SIRT1-dependent deacetylation. Supporting Evidence: Reactome:R-HSA-9825772 Deacetylation at these sites by SIRT1 promotes the interaction between MITF and HINT1
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:11672523 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.	KEEP AS NON CORE	Summary: SIRT1 reduces p53 transcriptional activity via deacetylation. Reason: Represents a downstream regulatory effect on p53 target genes. Supporting Evidence: PMID:11672523 Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53
GO:0034979 NAD-dependent protein lysine deacetylase activity	IMP PMID:11672523 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.	ACCEPT	Summary: SIRT1 deacetylates p53 in an NAD-dependent manner. Reason: Core enzymatic activity supported by direct deacetylation of p53. Supporting Evidence: PMID:11672523 binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue
GO:0140416 transcription regulator inhibitor activity	IDA PMID:11672523 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.	MODIFY	Summary: SIRT1 represses p53-mediated transcription; a corepressor term better captures this activity. Reason: Use transcription corepressor activity for this function instead of a generic inhibitor term. Proposed replacements: transcription corepressor activity Supporting Evidence: PMID:11672523 Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53
GO:0008047 enzyme activator activity	IDA PMID:18203716 Regulation of WRN protein cellular localization and enzymati...	MARK AS OVER ANNOTATED	Summary: SIRT1 reverses WRN acetylation effects on enzymatic activities via deacetylation rather than acting as a classical enzyme activator. Reason: The mechanism is deacetylation, not direct enzyme activation. Supporting Evidence: PMID:18203716 WRN acetylation decreases its helicase and exonuclease activities, and SIRT1 can reverse this effect.
GO:0035331 negative regulation of hippo signaling	IDA PMID:38512451 The alanyl-tRNA synthetase AARS1 moonlights as a lactyltrans...	KEEP AS NON CORE	Summary: SIRT1 delactylates YAP, counteracting lactylation-linked Hippo pathway activation. Reason: Context-specific modulation of YAP activity rather than a core SIRT1 function. Supporting Evidence: PMID:38512451 overexpression of SIRT1, but not of other members of this family, substantially reduced the lactylation levels of YAP
GO:0141208 NAD-dependent protein lysine delactylase activity	IDA PMID:38512451 The alanyl-tRNA synthetase AARS1 moonlights as a lactyltrans...	ACCEPT	Summary: SIRT1 removes lactylation from YAP and TEAD1 peptides in vitro. Reason: Direct delactylation activity is demonstrated with purified enzyme. Supporting Evidence: PMID:38512451 purified SIRT1, but not the H363Y mutant, eliminated lactylation of synthetic peptides of both YAP K90lac and TEAD1 K108lac
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:20203304 SIRT1 promotes proliferation and prevents senescence through...	KEEP AS NON CORE	Summary: SIRT1 can repress RNA polymerase II transcription through deacetylation of transcription factors; this is a downstream effect. Reason: Transcriptional repression is a contextual outcome of SIRT1 deacetylase activity rather than a core function. Supporting Evidence: PMID:11672523 Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IMP PMID:20203304 SIRT1 promotes proliferation and prevents senescence through...	KEEP AS NON CORE	Summary: SIRT1 promotes proteasome-mediated degradation of LKB1. Reason: Represents substrate-specific regulation of protein stability. Supporting Evidence: PMID:20203304 SIRT1 antagonized LKB1-dependent AMPK activation through promoting the deacetylation, ubiquitination and proteasome-mediated degradation of LKB1.
GO:0033558 protein lysine deacetylase activity	IMP PMID:20203304 SIRT1 promotes proliferation and prevents senescence through...	ACCEPT	Summary: SIRT1 deacetylates LKB1 as a protein lysine deacetylase. Reason: Direct deacetylation is reported. Supporting Evidence: PMID:20203304 SIRT1 antagonized LKB1-dependent AMPK activation through promoting the deacetylation, ubiquitination and proteasome-mediated degradation of LKB1.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:22918831 Autoacetylation of the MYST lysine acetyltransferase MOF pro...	ACCEPT	Summary: NAD-dependent protein lysine deacetylase activity is the core enzymatic function of SIRT1. Reason: Core molecular function supported by multiple experimental studies. Supporting Evidence: PMID:22918831 Autoacetylation of the MYST lysine acetyltransferase MOF protein. PMID:15692560 SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:17505061 Sirtuin 1 is required for antagonist-induced transcriptional...	KEEP AS NON CORE	Summary: SIRT1 is required for androgen antagonist-mediated transcriptional repression. Reason: Context-specific repression in androgen receptor signaling. Supporting Evidence: PMID:17505061 is required for androgen antagonist-mediated transcriptional repression and growth suppression
GO:0003714 transcription corepressor activity	IMP PMID:17505061 Sirtuin 1 is required for antagonist-induced transcriptional...	ACCEPT	Summary: SIRT1 acts as a transcriptional corepressor in AR antagonist responses. Reason: Direct evidence for corepressor function at AR-responsive promoters. Supporting Evidence: PMID:17505061 androgen receptor (AR) recruits SIRT1 and nuclear receptor corepressor to AR-responsive promoters and deacetylates histone H3 locally
GO:0017136 histone deacetylase activity, NAD-dependent	IDA PMID:12006491 Human SIR2 deacetylates p53 and antagonizes PML/p53-induced ...	ACCEPT	Summary: SIRT1 is an NAD-dependent histone deacetylase. Reason: Histone deacetylase activity is supported by multiple SIRT1 studies. Supporting Evidence: PMID:12006491 SIRT1 binds and deacetylates p53 PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0017136 histone deacetylase activity, NAD-dependent	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: SIRT1 is an NAD-dependent histone deacetylase that deacetylates H4K16 and H3K9. Reason: Core enzymatic activity in chromatin regulation. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0032041 histone H3K14 deacetylase activity, NAD-dependent	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: SIRT1 is an NAD-dependent histone deacetylase with H3-directed activity. Reason: Histone deacetylase activity is well supported and H3K14 specificity is consistent with SIRT1 histone targeting. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0033558 protein lysine deacetylase activity	IDA PMID:20027304 JNK1 phosphorylates SIRT1 and promotes its enzymatic activit...	ACCEPT	Summary: SIRT1 is an NAD-dependent protein deacetylase. Reason: Core molecular function supported by this study. Supporting Evidence: PMID:20027304 SIRT1 is a NAD-dependent deacetylase that regulates a variety of pathways
GO:0046969 histone H3K9 deacetylase activity, NAD-dependent	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: SIRT1 deacetylates histone H3K9 in vitro. Reason: Core histone substrate supported by biochemical evidence. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0046970 histone H4K16 deacetylase activity, NAD-dependent	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: SIRT1 deacetylates histone H4K16 in vitro. Reason: Core histone substrate supported by biochemical evidence. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0140937 histone H4K12 deacetylase activity, hydrolytic mechanism	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	UNDECIDED	Summary: H4K12 deacetylation is not described in the PMID:15469825 abstract. Reason: Additional evidence is required to support H4K12 specificity. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0141050 histone H3K deacetylase activity	IDA PMID:20027304 JNK1 phosphorylates SIRT1 and promotes its enzymatic activit...	ACCEPT	Summary: SIRT1 deacetylates histone H3 in cells. Reason: Histone H3 is a demonstrated substrate in this study. Supporting Evidence: PMID:20027304 resulting in selective activation of SIRT1, as measured by deacetylation of histone H3
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:29681526 A Designed Peptide Targets Two Types of Modifications of p53...	ACCEPT	Summary: Sirtuin deacetylase recruitment supports NAD-dependent protein lysine deacetylase activity. Reason: The study references sirtuin deacetylase activity in the p53 modification complex. Supporting Evidence: PMID:29681526 Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53.
GO:1901797 negative regulation of signal transduction by p53 class mediator	IDA PMID:29681526 A Designed Peptide Targets Two Types of Modifications of p53...	UNDECIDED	Summary: p53 suppression is described but the specific SIRT1-dependent mechanism is not explicit. Reason: The abstract does not directly attribute p53 signal suppression to SIRT1. Supporting Evidence: PMID:29681526 We found that Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53.
GO:0017136 histone deacetylase activity, NAD-dependent	IDA PMID:16079181 Evolutionarily conserved and nonconserved cellular localizat...	ACCEPT	Summary: SIRT1 shows in vitro deacetylase activity on histone H4 peptides. Reason: The study reports SIRT1-specific histone deacetylase activity. Supporting Evidence: PMID:16079181 SIRT1, but not the other two nuclear SIRT proteins, shows an in vitro deacetylase activity on histone H4 and p53 peptides
GO:1990404 NAD+-protein mono-ADP-ribosyltransferase activity	TAS NOT PMID:17456799 Sirtuin functions in health and disease.	UNDECIDED	Summary: Review notes that some sirtuins have ADP-ribosyltransferase activity but does not specify SIRT1. Reason: The reference does not provide SIRT1-specific evidence to support or refute this activity. Supporting Evidence: PMID:17456799 Certain sirtuins have in addition an ADP-ribosyltransferase activity.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:32538779 Synergy between SIRT1 and SIRT6 helps recognize DNA breaks a...	ACCEPT	Summary: SIRT1 deacetylates SIRT6 at K33 in the DNA damage response. Reason: Direct deacetylation of a protein substrate is reported. Supporting Evidence: PMID:32538779 SIRT1 deacetylates SIRT6 at residue K33
GO:2000781 positive regulation of double-strand break repair	IDA PMID:32538779 Synergy between SIRT1 and SIRT6 helps recognize DNA breaks a...	KEEP AS NON CORE	Summary: SIRT1 supports repair signaling by enabling SIRT6 recruitment to DNA breaks. Reason: DNA repair promotion is a downstream effect of SIRT1 activity. Supporting Evidence: PMID:32538779 Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice.
GO:0005829 cytosol	IDA PMID:20027304 JNK1 phosphorylates SIRT1 and promotes its enzymatic activit...	ACCEPT	Summary: SIRT1 localizes to cytoplasmic compartments. Reason: Direct immunostaining shows cytoplasmic localization. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:30193097 Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Tog...	ACCEPT	Summary: SIRT1 deacetylates PCK1, supporting NAD-dependent protein lysine deacetylase activity. Reason: The abstract directly states SIRT1 deacetylates a protein substrate (PCK1). Supporting Evidence: PMID:30193097 SIRT1 deacetylates PCK1
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated...	ACCEPT	Summary: SIRT1 deacetylates FOXO1 as an NAD-dependent protein lysine deacetylase. Reason: Direct deacetylation of a protein substrate is reported. Supporting Evidence: PMID:15692560 SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:23142079 The deacetylase Sirt6 activates the acetyltransferase GCN5 a...	ACCEPT	Summary: SIRT1 is noted as a deacetylase controlling PGC-1α acetylation. Reason: The abstract describes SIRT1 as the deacetylase that controls PGC-1α acetylation state. Supporting Evidence: PMID:23142079 PGC-1α's activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1.
GO:0045722 positive regulation of gluconeogenesis	IDA PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated...	KEEP AS NON CORE	Summary: SIRT1 influences gluconeogenic gene expression via FOXO1. Reason: Gluconeogenesis regulation is a downstream metabolic effect. Supporting Evidence: PMID:15692560 SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity.
GO:0045722 positive regulation of gluconeogenesis	IDA PMID:23142079 The deacetylase Sirt6 activates the acetyltransferase GCN5 a...	KEEP AS NON CORE	Summary: SIRT1 regulates gluconeogenic gene expression via PGC-1α acetylation control. Reason: Gluconeogenesis regulation is a downstream metabolic effect. Supporting Evidence: PMID:23142079 PGC-1α's activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1.
GO:0051658 maintenance of nucleus location	IDA PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated...	REMOVE	Summary: Maintenance of nucleus location is not described in this study. Reason: No evidence for nuclear positioning in the FOXO1 deacetylation study. Supporting Evidence: PMID:15692560 SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity.
GO:0017136 histone deacetylase activity, NAD-dependent	IDA PMID:28497810 Class I histone deacetylases are major histone decrotonylase...	ACCEPT	Summary: SIRT1 is an NAD-dependent histone deacetylase. Reason: Histone deacetylase activity is supported by multiple SIRT1 studies. Supporting Evidence: PMID:28497810 class I histone deacetylases (HDACs) rather than sirtuin family deacetylases (SIRTs) are the major histone decrotonylases PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:29765047 Tip60-mediated lipin 1 acetylation and ER translocation dete...	ACCEPT	Summary: SIRT1 is described as a deacetylase in this study, supporting NAD-dependent protein lysine deacetylase activity. Reason: The abstract explicitly identifies Sirt1 as the deacetylase repressing TAG synthesis. Supporting Evidence: PMID:29765047 repressed by deacetylase Sirt1.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:30409912 Dynamic acetylation of the kinetochore-associated protein HE...	ACCEPT	Summary: SIRT1 reverses TIP60-mediated HEC1 acetylation, supporting NAD-dependent protein lysine deacetylase activity. Reason: The abstract notes SIRT1 specifically reverses HEC1 acetylation. Supporting Evidence: PMID:30409912 TIP60-mediated acetylation was specifically reversed by sirtuin 1 (SIRT1).
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:32034146 Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex as...	ACCEPT	Summary: NAD-dependent protein lysine deacetylase activity is the core enzymatic function of SIRT1. Reason: Core molecular function supported by multiple experimental studies. Supporting Evidence: PMID:32034146 TIP60, also known as KAT5, a haplo-insufficient tumor suppressor, directly acetylates XPF PMID:15692560 SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity.
GO:0160012 histone decrotonylase activity, NAD-dependent	IDA PMID:28497810 Class I histone deacetylases are major histone decrotonylase...	REMOVE	Summary: This study indicates sirtuins are not the major histone decrotonylases. Reason: Evidence points to class I HDACs, not SIRT1, as major decrotonylases. Supporting Evidence: PMID:28497810 class I histone deacetylases (HDACs) rather than sirtuin family deacetylases (SIRTs) are the major histone decrotonylases
GO:0010868 negative regulation of triglyceride biosynthetic process	IDA PMID:29765047 Tip60-mediated lipin 1 acetylation and ER translocation dete...	KEEP AS NON CORE	Summary: SIRT1 represses TAG synthesis in this system. Reason: The study reports repression of TAG synthesis by SIRT1, a metabolic regulation role rather than a core function. Supporting Evidence: PMID:29765047 synthesis, which is repressed by deacetylase Sirt1.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:20100829 SIRT1 regulates autoacetylation and histone acetyltransferas...	ACCEPT	Summary: SIRT1 deacetylates TIP60 as an NAD-dependent protein lysine deacetylase. Reason: Direct deacetylation of TIP60 is reported. Supporting Evidence: PMID:20100829 we identified SIRT1 that specifically deacetylates TIP60 and negatively regulates TIP60 activity in vivo.
GO:0140861 DNA repair-dependent chromatin remodeling	IDA PMID:20100829 SIRT1 regulates autoacetylation and histone acetyltransferas...	UNDECIDED	Summary: DNA repair-dependent chromatin remodeling is not directly demonstrated here. Reason: The abstract focuses on TIP60 autoacetylation and SIRT1 deacetylation, not chromatin remodeling. Supporting Evidence: PMID:20100829 TIP60 is autoacetylated in response to UV damage
GO:0140297 DNA-binding transcription factor binding	IPI PMID:20955178 Regulation of unfolded protein response modulator XBP1s by a...	KEEP AS NON CORE	Summary: SIRT1 binds the transcription factor XBP1s for deacetylation. Reason: Represents a context-specific transcription factor interaction. Supporting Evidence: PMID:20955178 In the present study, we demonstrate that XBP1s is a target of acetylation and deacetylation mediated by p300 and SIRT1 (sirtuin 1) respectively
GO:0140297 DNA-binding transcription factor binding	IPI PMID:23382074 A high-confidence interaction map identifies SIRT1 as a medi...	KEEP AS NON CORE	Summary: SIRT1 interacts with transcription factors in specific contexts. Reason: Represents a context-specific transcription factor interaction. Supporting Evidence: PMID:23382074 Feb 4. A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.
GO:0005515 protein binding	IPI PMID:31722219 CCDC84 Acetylation Oscillation Regulates Centrosome Duplicat...	REMOVE	Summary: Generic protein binding from this study is not informative for SIRT1 function. Reason: Specific interactions and enzymatic activity are more informative than a generic binding term. Supporting Evidence: PMID:31722219 the acetylation state of CCDC84 at lysine 31 is regulated by the deacetylase SIRT1
GO:0006476 protein deacetylation	IDA PMID:31722219 CCDC84 Acetylation Oscillation Regulates Centrosome Duplicat...	ACCEPT	Summary: SIRT1 deacetylates CCDC84 as a protein deacetylase. Reason: Direct evidence that SIRT1 regulates acetylation state of a substrate. Supporting Evidence: PMID:31722219 the acetylation state of CCDC84 at lysine 31 is regulated by the deacetylase SIRT1
GO:0010824 regulation of centrosome duplication	IDA PMID:31722219 CCDC84 Acetylation Oscillation Regulates Centrosome Duplicat...	KEEP AS NON CORE	Summary: CCDC84 acetylation state affects centrosome duplication, with SIRT1 as the deacetylase. Reason: Centrosome duplication effects are downstream of SIRT1 deacetylation activity. Supporting Evidence: PMID:31722219 CCDC84 Acetylation Oscillation Regulates Centrosome Duplication by Modulating HsSAS-6 Degradation
GO:0106230 protein depropionylation	ISS GO_REF:0000024	UNDECIDED	Summary: Evidence for SIRT1 depropionylation activity is not specified in this reference. Reason: GO_REF:0000024 does not provide direct experimental support here.
GO:0106231 NAD-dependent protein-lysine depropionylase activity	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 exhibits NAD-dependent deacylase activities including depropionylation in some contexts. Reason: Downstream enzymatic activity beyond core deacetylation.
GO:0045722 positive regulation of gluconeogenesis	IDA PMID:30193097 Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Tog...	KEEP AS NON CORE	Summary: SIRT1 promotes gluconeogenic activity via PCK1 deacetylation. Reason: Gluconeogenesis regulation is a downstream metabolic effect. Supporting Evidence: PMID:30193097 Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Toggles Enzyme Activity between Gluconeogenic and Anaplerotic Reactions.
GO:0005515 protein binding	IPI PMID:29656858 A Recurrent De Novo PACS2 Heterozygous Missense Variant Caus...	REMOVE	Summary: This paper is about PACS2 variants and does not provide SIRT1 binding evidence. Reason: No SIRT1 interactions are described. Supporting Evidence: PMID:29656858 A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.
GO:0007179 transforming growth factor beta receptor signaling pathway	IDA PMID:23960241 MicroRNA-mediated epigenetic silencing of sirtuin1 contribut...	REMOVE	Summary: This study links TGF-β signaling to Sirt1 silencing, but does not place SIRT1 within the receptor signaling pathway. Reason: SIRT1 is a downstream target rather than a component of TGF-β receptor signaling. Supporting Evidence: PMID:23960241 MeCP2 inhibited endothelial angiogenic characteristics partly by epigenetic silencing of Sirt1.
GO:0043536 positive regulation of blood vessel endothelial cell migration	IDA PMID:23960241 MicroRNA-mediated epigenetic silencing of sirtuin1 contribut...	KEEP AS NON CORE	Summary: Sirt1 influences endothelial angiogenic functions affected by TGF-β/MeCP2. Reason: Context-specific effect on endothelial migration/angiogenic function. Supporting Evidence: PMID:23960241 involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells.
GO:0045766 positive regulation of angiogenesis	IDA PMID:23960241 MicroRNA-mediated epigenetic silencing of sirtuin1 contribut...	KEEP AS NON CORE	Summary: Sirt1 contributes to angiogenic functions in endothelial cells. Reason: Represents downstream functional impact rather than core enzymatic role. Supporting Evidence: PMID:23960241 involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells.
GO:0033558 protein lysine deacetylase activity	IMP PMID:20424141 MicroRNA-34a induces endothelial progenitor cell senescence ...	ACCEPT	Summary: Sirt1 modulation affects acetylation status of FOXO1, consistent with protein lysine deacetylase activity. Reason: Changes in Sirt1 levels alter acetylated FOXO1. Supporting Evidence: PMID:20424141 overexpression of miR-34a increased the level of Sirt1 effector-acetylated forkhead box O transcription factors 1 (FoxO1)
GO:0045766 positive regulation of angiogenesis	IMP PMID:20424141 MicroRNA-34a induces endothelial progenitor cell senescence ...	KEEP AS NON CORE	Summary: Sirt1 suppression impairs EPC-mediated angiogenesis. Reason: Angiogenesis phenotype is downstream of Sirt1 regulation. Supporting Evidence: PMID:20424141 miR-34a inhibits EPC-mediated angiogenesis by inducing senescence via suppressing Sirt1.
GO:2000773 negative regulation of cellular senescence	IMP PMID:20424141 MicroRNA-34a induces endothelial progenitor cell senescence ...	KEEP AS NON CORE	Summary: Sirt1 suppression induces senescence in EPCs. Reason: Senescence regulation is context-specific. Supporting Evidence: PMID:20424141 miR-34a inhibits EPC-mediated angiogenesis by inducing senescence via suppressing Sirt1.
GO:0045766 positive regulation of angiogenesis	IDA PMID:25217442 Vascular importance of the miR-212/132 cluster.	KEEP AS NON CORE	Summary: The study links miR-212/132 effects to suppression of SIRT1 and impaired endothelial function, but does not directly show SIRT1 driving angiogenesis. Reason: Evidence is indirect but supports a context-specific role in angiogenic regulation. Supporting Evidence: PMID:25217442 suppression of important endothelial genes such as GAB1 and SIRT1
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:12837246 Multiple tumor suppressor pathways negatively regulate telom...	KEEP AS NON CORE	Summary: SIRT1 influences transcriptional regulation in specific contexts. Reason: Context-specific transcriptional modulation rather than a core function. Supporting Evidence: PMID:12837246 Multiple tumor suppressor pathways negatively regulate telomerase.
GO:0042981 regulation of apoptotic process	IMP PMID:19934257 SIRT1 deacetylates APE1 and regulates cellular base excision...	KEEP AS NON CORE	Summary: SIRT1 influences apoptosis during genotoxic stress via APE1 regulation. Reason: Apoptosis effects are downstream of DNA repair modulation. Supporting Evidence: PMID:19934257 sensitizing cells to death induced by genotoxic stress
GO:0005634 nucleus	IDA PMID:20167603 DYRK1A and DYRK3 promote cell survival through phosphorylati...	ACCEPT	Summary: SIRT1 localizes to the nucleus. Reason: Nuclear localization is well supported in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0010883 regulation of lipid storage	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences regulation of lipid storage. Reason: Downstream metabolic regulation rather than a core function.
GO:0030225 macrophage differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates macrophage differentiation in broader immune contexts. Reason: Downstream immune regulation rather than a core function.
GO:0060907 positive regulation of macrophage cytokine production	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates macrophage cytokine production. Reason: Downstream immune regulation rather than a core function.
GO:1904179 positive regulation of adipose tissue development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences adipose tissue development. Reason: Downstream metabolic regulation rather than a core function.
GO:0045766 positive regulation of angiogenesis	IMP PMID:24048733 Antidicer RNAse activity of monocyte chemotactic protein-ind...	KEEP AS NON CORE	Summary: SIRT1 induction is reported as part of MCPIP-driven angiogenic signaling. Reason: This reflects a context-specific angiogenic pathway rather than a core SIRT1 function. Supporting Evidence: PMID:24048733 MCPIP-induced angiogenesis is mediated via hypoxia-inducible factor (HIF-1α), vascular endothelial growth factor (VEGF), and silent information regulator (SIRT-1) induction
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 positively modulates PI3K/AKT signaling in some contexts. Reason: Downstream signaling modulation rather than a core function.
GO:0090335 regulation of brown fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences brown fat cell differentiation. Reason: Downstream metabolic regulation rather than a core function.
GO:0033210 leptin-mediated signaling pathway	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences leptin-mediated signaling. Reason: Downstream metabolic signaling role rather than a core function.
GO:0044321 response to leptin	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 participates in leptin response contexts. Reason: Downstream metabolic signaling role rather than a core function.
GO:0001938 positive regulation of endothelial cell proliferation	IMP PMID:20203304 SIRT1 promotes proliferation and prevents senescence through...	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:20203304 2010 Mar 4. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells.
GO:0005515 protein binding	IPI PMID:21030595 HDAC3 is negatively regulated by the nuclear protein DBC1.	REMOVE	Summary: Generic protein binding annotation is uninformative. Reason: Generic protein binding annotation is uninformative. More specific annotations capture the biologically relevant interactions. Supporting Evidence: PMID:21030595 2010 Oct 28. HDAC3 is negatively regulated by the nuclear protein DBC1.
GO:0005515 protein binding	IPI PMID:25661920 CCAR2 negatively regulates nuclear receptor LXRα by competin...	REMOVE	Summary: The study focuses on CCAR2 competition with SIRT1; generic protein binding is uninformative. Reason: A specific SIRT1 interaction context is described, making the generic binding term unhelpful. Supporting Evidence: PMID:25661920 CCAR2 negatively regulates nuclear receptor LXRα by competing with SIRT1 deacetylase.
GO:0006476 protein deacetylation	IMP PMID:24824780 MCC inhibits beta-catenin transcriptional activity by seques...	ACCEPT	Summary: SIRT1 inhibition reverses MCC-induced deacetylation of β-catenin. Reason: Direct deacetylation effect is supported in this context. Supporting Evidence: PMID:24824780 Treatment of cells with the SIRT1 inhibitor Nicotinamide reverses MCC-induced deacetylation of β-cat K49.
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:20074560 Repression of estrogen receptor beta function by putative tu...	KEEP AS NON CORE	Summary: DBC1 modulation implicates SIRT1 in transcriptional repression contexts. Reason: Represents context-specific transcriptional repression rather than a core function. Supporting Evidence: PMID:20074560 depletion of the endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1.
GO:0016922 nuclear receptor binding	IPI PMID:24043310 SIRT4 represses peroxisome proliferator-activated receptor α...	REMOVE	Summary: This paper is about SIRT4 and PPARα, not SIRT1. Reason: No SIRT1 nuclear receptor binding evidence is provided. Supporting Evidence: PMID:24043310 SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:20955178 Regulation of unfolded protein response modulator XBP1s by a...	KEEP AS NON CORE	Summary: SIRT1 inhibits XBP1s-dependent transcription. Reason: Downstream effect of deacetylating a specific transcription factor. Supporting Evidence: PMID:20955178 SIRT1 deacetylates XBP1s and inhibits its transcriptional activity
GO:0005634 nucleus	IDA PMID:20955178 Regulation of unfolded protein response modulator XBP1s by a...	ACCEPT	Summary: SIRT1 is nuclear in studies of XBP1s regulation. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0032922 circadian regulation of gene expression	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates circadian clock components through deacetylation. Reason: Circadian regulation is a downstream outcome of SIRT1 activity.
GO:0006476 protein deacetylation	IDA PMID:18662546 SIRT1 regulates circadian clock gene expression through PER2...	ACCEPT	Summary: SIRT1 promotes PER2 deacetylation, supporting protein deacetylation activity. Reason: The abstract reports SIRT1 deacetylation of PER2. Supporting Evidence: PMID:18662546 SIRT1 regulates circadian clock gene expression through PER2 deacetylation.
GO:0032922 circadian regulation of gene expression	IMP PMID:18662546 SIRT1 regulates circadian clock gene expression through PER2...	KEEP AS NON CORE	Summary: SIRT1 regulates circadian clock gene expression through PER2 deacetylation (PMID:18662546). While the experimental evidence supports clock regulation, SIRT1 has broad substrate specificity and clock proteins are just one of many targets. Reason: The IMP evidence from PMID:18662546 specifically demonstrates SIRT1 involvement in circadian regulation. However, this is one of many downstream effects of SIRT1 deacetylase activity on diverse substrates. Not a core function. Supporting Evidence: PMID:18662546 SIRT1, an NAD(+)-dependent protein deacetylase, is required for high-magnitude circadian transcription of several core clock genes, including Bmal1, Rorgamma, Per2, and Cry1.
GO:0005515 protein binding	IPI PMID:23382074 A high-confidence interaction map identifies SIRT1 as a medi...	REMOVE	Summary: Generic protein binding is uninformative relative to specific interaction terms. Reason: Specific enzyme-binding interaction is more informative. Supporting Evidence: PMID:23382074 as a SIRT1-interacting partner
GO:0019899 enzyme binding	IPI PMID:23382074 A high-confidence interaction map identifies SIRT1 as a medi...	ACCEPT	Summary: SIRT1 interacts with the deubiquitinating enzyme USP22. Reason: Direct interaction with an enzyme partner is reported. Supporting Evidence: PMID:23382074 as a SIRT1-interacting partner
GO:1990254 keratin filament binding	IPI PMID:23382074 A high-confidence interaction map identifies SIRT1 as a medi...	REMOVE	Summary: Keratin filament binding is not described in this study. Reason: No evidence for keratin filament binding. Supporting Evidence: PMID:23382074 as a SIRT1-interacting partner
GO:0000785 chromatin	IDA PMID:22956909 Dynamic distribution of linker histone H1.5 in cellular diff...	ACCEPT	Summary: SIRT1 binds chromatin at H1.5 target loci in differentiated cells. Reason: SIRT1 binding is required for chromatin compaction at H1.5 targets. Supporting Evidence: PMID:22956909 H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction.
GO:0006325 chromatin organization	IMP PMID:22956909 Dynamic distribution of linker histone H1.5 in cellular diff...	KEEP AS NON CORE	Summary: SIRT1 contributes to chromatin compaction at H1.5 target loci. Reason: Represents context-specific chromatin organization effects. Supporting Evidence: PMID:22956909 H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction.
GO:0042393 histone binding	IPI PMID:22956909 Dynamic distribution of linker histone H1.5 in cellular diff...	ACCEPT	Summary: SIRT1 associates with histone H1.5-containing chromatin. Reason: Histone association supports histone binding. Supporting Evidence: PMID:22956909 H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction.
GO:0010629 negative regulation of gene expression	IMP PMID:17916362 Sirt1 modulates premature senescence-like phenotype in human...	MARK AS OVER ANNOTATED	Summary: Gene expression changes are specific (PAI-1 and eNOS), not a broad repression program. Reason: The term is too general for the evidence provided. Supporting Evidence: PMID:17916362 increased PAI-1 expression and decreased both protein expression and activity of eNOS.
GO:0090400 stress-induced premature senescence	IMP PMID:17916362 Sirt1 modulates premature senescence-like phenotype in human...	KEEP AS NON CORE	Summary: Sirt1 inhibition induces premature senescence-like phenotype in endothelial cells. Reason: Senescence effects are downstream of Sirt1 activity. Supporting Evidence: PMID:17916362 Sirt1 inhibition increased p53 acetylation and induced premature senescence-like phenotype
GO:1901984 negative regulation of protein acetylation	IMP PMID:17916362 Sirt1 modulates premature senescence-like phenotype in human...	ACCEPT	Summary: Sirt1 normally counteracts protein acetylation, as inhibition increases p53 acetylation. Reason: Direct evidence of increased acetylation upon Sirt1 inhibition. Supporting Evidence: PMID:17916362 Treatment with sirtinol or Sirt1 siRNA increased acetylation of p53
GO:0042542 response to hydrogen peroxide	IDA PMID:19934257 SIRT1 deacetylates APE1 and regulates cellular base excision...	KEEP AS NON CORE	Summary: Genotoxic stress including H2O2 affects APE1 acetylation regulated by SIRT1. Reason: Represents stress-context regulation rather than a core function. Supporting Evidence: PMID:19934257 H2O2 led to an increase in acetylation of APE1
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3371467	ACCEPT	Summary: SIRT1 is nuclear in contexts including HSF1 regulation. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3371518	ACCEPT	Summary: SIRT1 is nuclear in HSF1 regulatory contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3371537	ACCEPT	Summary: SIRT1 is nuclear in DBC1 regulatory contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-427514	ACCEPT	Summary: SIRT1 is nuclear in eNoSC chromatin regulation contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-427527	ACCEPT	Summary: SIRT1 is nuclear in eNoSC chromatin regulation contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-427528	ACCEPT	Summary: SIRT1 is nuclear in eNoSC complex contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9620532	ACCEPT	Summary: SIRT1 is nuclear in FOXO3 regulation contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9765850	ACCEPT	Summary: SIRT1 is nuclear in transcriptional regulation contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9825772	ACCEPT	Summary: SIRT1 is nuclear in HINT1-related regulatory contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9854916	ACCEPT	Summary: SIRT1 is nuclear in transcriptional regulation contexts. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	ISS PMID:11672522 Negative control of p53 by Sir2alpha promotes cell survival ...	KEEP AS NON CORE	Summary: Sir2alpha represses p53-dependent apoptosis under DNA damage stress. Reason: The effect is context-specific p53-dependent apoptosis modulation rather than a core SIRT1 function. Supporting Evidence: PMID:11672522 Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress
GO:1902176 negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	IMP PMID:17317627 Phosphorylation of HuR by Chk2 regulates SIRT1 expression.	REMOVE	Summary: This paper focuses on HuR regulation of SIRT1 expression under oxidative stress, not direct apoptosis pathway regulation. Reason: No direct evidence for negative regulation of oxidative stress-induced intrinsic apoptosis by SIRT1 is provided. Supporting Evidence: PMID:17317627 SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival.
GO:0033558 protein lysine deacetylase activity	IDA PMID:23056314 Angiogenesis inhibitor vasohibin-1 enhances stress resistanc...	ACCEPT	Summary: Protein lysine deacetylase activity is a core function of SIRT1. Reason: Core molecular function supported by multiple SIRT1 studies. Supporting Evidence: PMID:23056314 VASH1 augmented the synthesis of sirtuin 1 (SIRT1)
GO:0033558 protein lysine deacetylase activity	IMP PMID:20670893 SIRT1 regulates UV-induced DNA repair through deacetylating ...	ACCEPT	Summary: SIRT1 deacetylates XPA, supporting protein lysine deacetylase activity. Reason: The study reports direct deacetylation of XPA by SIRT1. Supporting Evidence: PMID:20670893 SIRT1 deacetylates XPA
GO:0070914 UV-damage excision repair	IMP PMID:20670893 SIRT1 regulates UV-induced DNA repair through deacetylating ...	KEEP AS NON CORE	Summary: SIRT1 regulates the NER pathway in UV-damage excision repair contexts. Reason: SIRT1 modulates NER via XPA deacetylation, but this is a specific downstream process rather than a core function. Supporting Evidence: PMID:20670893 SIRT1 regulates NER pathway
GO:0035358 regulation of peroxisome proliferator activated receptor signaling pathway	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates PPAR signaling in metabolic contexts. Reason: Downstream metabolic regulation rather than a core function.
GO:0010875 positive regulation of cholesterol efflux	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences cholesterol efflux. Reason: Downstream metabolic regulation rather than a core function.
GO:0031648 protein destabilization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 can influence protein stability in specific contexts. Reason: Downstream regulatory effect rather than a core function.
GO:0035356 intracellular triglyceride homeostasis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 contributes to intracellular triglyceride homeostasis. Reason: Downstream metabolic regulation rather than a core function.
GO:0042632 cholesterol homeostasis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 contributes to cholesterol homeostasis. Reason: Downstream metabolic regulation rather than a core function.
GO:0031393 negative regulation of prostaglandin biosynthetic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates prostaglandin biosynthesis in specific contexts. Reason: Downstream regulatory effect rather than a core function.
GO:0070857 regulation of bile acid biosynthetic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences bile acid biosynthesis regulation. Reason: Downstream metabolic regulation rather than a core function.
GO:2000111 positive regulation of macrophage apoptotic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates macrophage apoptotic processes. Reason: Downstream immune regulation rather than a core function.
GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates TGF-beta signaling in specific contexts. Reason: Downstream signaling regulation rather than a core function.
GO:0034391 regulation of smooth muscle cell apoptotic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences smooth muscle cell apoptotic processes. Reason: Downstream cell-type-specific regulation rather than a core function.
GO:2000481 positive regulation of cAMP-dependent protein kinase activity	IMP PMID:18687677 SIRT1 modulation of the acetylation status, cytosolic locali...	REMOVE	Summary: The study addresses LKB1/AMPK activation, not cAMP-dependent protein kinase activity. Reason: The abstract discusses AMP-activated protein kinase signaling rather than cAMP-dependent protein kinase regulation. Supporting Evidence: PMID:18687677 AMP-activated protein kinase (AMPK)
GO:2000773 negative regulation of cellular senescence	IDA PMID:20203304 SIRT1 promotes proliferation and prevents senescence through...	KEEP AS NON CORE	Summary: Increasing SIRT1 levels blocks LKB1-induced cellular senescence. Reason: Senescence regulation is context-specific downstream biology. Supporting Evidence: PMID:20203304 Overexpression of LKB1 promoted cellular senescence and retarded endothelial proliferation, which could be blocked by increasing SIRT1 levels.
GO:2000774 positive regulation of cellular senescence	IDA PMID:18687677 SIRT1 modulation of the acetylation status, cytosolic locali...	REMOVE	Summary: This paper focuses on LKB1 deacetylation and AMPK activation, not cellular senescence. Reason: There is no reported senescence phenotype in the abstract; the evidence centers on AMPK signaling. Supporting Evidence: PMID:18687677 AMP-activated protein kinase (AMPK)
GO:0032007 negative regulation of TOR signaling	IMP PMID:20169165 SIRT1 negatively regulates the mammalian target of rapamycin...	KEEP AS NON CORE	Summary: SIRT1 negatively regulates mTOR signaling via TSC2. Reason: mTOR pathway regulation is a downstream signaling role rather than a core enzymatic function. Supporting Evidence: PMID:20169165 SIRT1 negatively regulates the mammalian target of rapamycin.
GO:0043124 negative regulation of canonical NF-kappaB signal transduction	IDA PMID:17680780 Sirt1 interacts with transducin-like enhancer of split-1 to ...	KEEP AS NON CORE	Summary: Sirt1 and TLE1 repress NF-kappaB activity. Reason: NF-kappaB repression is a specific downstream regulatory effect of SIRT1. Supporting Evidence: PMID:17680780 Sirt1 and TLE1 repress NF-kappaB activity.
GO:0001934 positive regulation of protein phosphorylation	ISS GO_REF:0000024	UNDECIDED	Summary: No direct evidence for SIRT1 in positive regulation of protein phosphorylation is provided here. Reason: GO_REF:0000024 does not provide direct experimental support.
GO:0032868 response to insulin	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates insulin response through deacetylation of insulin signaling regulators. Reason: Downstream signaling modulation rather than a core function.
GO:0046628 positive regulation of insulin receptor signaling pathway	IDA PMID:21241768 Phosphoinositide 3-kinase as a novel functional target for t...	KEEP AS NON CORE	Summary: SIRT1 positively modulates insulin signaling via PI3K in muscle cells. Reason: This is a context-specific signaling modulation downstream of SIRT1 activity. Supporting Evidence: PMID:21241768 SIRT1 as a positive modulator of insulin signaling in muscle cells through PI3K
GO:0002821 positive regulation of adaptive immune response	IDA PMID:21890893 SIRT1 links CIITA deacetylation to MHC II activation.	MARK AS OVER ANNOTATED	Summary: The evidence supports SIRT1-enhanced MHC II transcription, a specific step within adaptive immunity. Reason: The study demonstrates MHC II transactivation rather than broad positive regulation of the adaptive immune response. Supporting Evidence: PMID:21890893 SIRT1 activation augments MHC II transcription
GO:0045348 positive regulation of MHC class II biosynthetic process	IDA PMID:21890893 SIRT1 links CIITA deacetylation to MHC II activation.	KEEP AS NON CORE	Summary: SIRT1 activation augments MHC II transcription via CIITA. Reason: This reflects immune regulation downstream of SIRT1 activity rather than a core enzymatic function. Supporting Evidence: PMID:21890893 SIRT1 activation augments MHC II transcription
GO:0035098 ESC/E(Z) complex	IDA PMID:15684044 Composition and histone substrates of polycomb repressive gr...	KEEP AS NON CORE	Summary: SirT1 is reported as a component of a PRC4 polycomb complex. Reason: The study describes SIRT1 in a polycomb complex context, which is not a core function. Supporting Evidence: PMID:15684044 PRC4, that contains the NAD+-dependent histone deacetylase SirT1
GO:0000012 single strand break repair	IMP PMID:20097625 Role of SIRT1 in homologous recombination.	REMOVE	Summary: This study demonstrates SIRT1 promotion of homologous recombination, not single-strand break repair. Reason: The evidence is specific to double-strand break repair via HR. Supporting Evidence: PMID:20097625 SIRT1 activity promotes homologous recombination (HR) in human cells.
GO:0001678 intracellular glucose homeostasis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 participates in glucose homeostasis regulation. Reason: Downstream metabolic regulation rather than a core function.
GO:0010906 regulation of glucose metabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 modulates glucose metabolic processes. Reason: Downstream metabolic regulation rather than a core function.
GO:0055089 fatty acid homeostasis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences fatty acid homeostasis. Reason: Downstream metabolic regulation rather than a core function.
GO:0016239 positive regulation of macroautophagy	IDA PMID:18296641 A role for the NAD-dependent deacetylase Sirt1 in the regula...	KEEP AS NON CORE	Summary: Increased Sirt1 expression stimulates autophagy and Sirt1 deficiency impairs autophagy activation. Reason: Autophagy regulation is a downstream process rather than the core deacetylase activity. Supporting Evidence: PMID:18296641 transient increased expression of Sirt1 is sufficient to stimulate basal rates of autophagy.
GO:0000720 pyrimidine dimer repair by nucleotide-excision repair	IMP PMID:21149730 Regulation of global genome nucleotide excision repair by SI...	KEEP AS NON CORE	Summary: SIRT1 regulates global genome nucleotide excision repair via XPC. Reason: The paper supports NER involvement but this is a specific downstream DNA repair role. Supporting Evidence: PMID:21149730 SIRT1 impairs global genome NER
GO:0000731 DNA synthesis involved in DNA repair	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 participates in DNA repair-related synthesis contexts. Reason: Downstream DNA repair role rather than a core function.
GO:0042326 negative regulation of phosphorylation	IMP PMID:17612497 SIRT1 regulates the function of the Nijmegen breakage syndro...	REMOVE	Summary: The study indicates SIRT1 is required for NBS1 phosphorylation, not negative regulation of phosphorylation. Reason: Evidence shows SIRT1 supports phosphorylation rather than suppressing it. Supporting Evidence: PMID:17612497 required for ionizing radiation-induced NBS1 Ser343 phosphorylation.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP PMID:21149730 Regulation of global genome nucleotide excision repair by SI...	KEEP AS NON CORE	Summary: SIRT1 modulates an AKT-dependent localization step but direct negative regulation of PI3K/AKT signaling is not shown. Reason: The evidence is indirect but indicates a regulatory role in this signaling context. Supporting Evidence: PMID:21149730 reducing AKT-dependent nuclear localization
GO:0071479 cellular response to ionizing radiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 participates in responses to ionizing radiation. Reason: Downstream stress-response role rather than a core function.
GO:0043065 positive regulation of apoptotic process	IDA PMID:15152190 Modulation of NF-kappaB-dependent transcription and cell sur...	KEEP AS NON CORE	Summary: SIRT1 activity augments TNFalpha-induced apoptosis. Reason: The apoptotic effect is stimulus-specific and not a core function. Supporting Evidence: PMID:15152190 augments apoptosis in response to TNFalpha
GO:0071356 cellular response to tumor necrosis factor	IDA PMID:15152190 Modulation of NF-kappaB-dependent transcription and cell sur...	KEEP AS NON CORE	Summary: SIRT1 sensitizes cells to TNFalpha-induced apoptosis. Reason: This reflects a context-specific TNF response rather than a core SIRT1 function. Supporting Evidence: PMID:15152190 sensitization of cells to TNFalpha-induced apoptosis.
GO:0007346 regulation of mitotic cell cycle	IDA PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated...	REMOVE	Summary: Mitotic cell cycle regulation is not described in this study. Reason: No evidence for mitotic cell cycle regulation in this FOXO1 study. Supporting Evidence: PMID:15692560 SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity.
GO:0043066 negative regulation of apoptotic process	IMP PMID:16892051 Interactions between E2F1 and SirT1 regulate apoptotic respo...	KEEP AS NON CORE	Summary: SirT1 knockdown increases E2F1 apoptotic functions, indicating SirT1 suppresses apoptosis in this context. Reason: The effect is context-specific regulation of E2F1-mediated apoptosis. Supporting Evidence: PMID:16892051 Knockdown of SirT1 by small interference RNA (siRNA) increases E2F1 transcriptional and apoptotic functions.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:15692560 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated...	KEEP AS NON CORE	Summary: SIRT1 inhibits FOXO1 transcriptional activity via deacetylation. Reason: Downstream effect on a specific transcription factor, not core function. Supporting Evidence: PMID:15692560 SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity.
GO:0001525 angiogenesis	IDA PMID:20620956 Sirtuin 1 modulates cellular responses to hypoxia by deacety...	KEEP AS NON CORE	Summary: SIRT1 negatively affects angiogenesis in vivo. Reason: The study reports an effect on angiogenesis downstream of SIRT1 regulation of HIF-1alpha, which is not a core function. Supporting Evidence: PMID:20620956 SIRT1 has negative effects on tumor growth and angiogenesis.
GO:0006979 response to oxidative stress	IDA PMID:14976264 Stress-dependent regulation of FOXO transcription factors by...	KEEP AS NON CORE	Summary: SIRT1 shifts FOXO3 responses toward resistance to oxidative stress. Reason: This is a downstream stress-response outcome of SIRT1 activity. Supporting Evidence: PMID:14976264 SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress
GO:0016567 protein ubiquitination	IDA PMID:21841822 Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-media...	KEEP AS NON CORE	Summary: SIRT1 deacetylation of FOXO3 promotes ubiquitination and degradation. Reason: The evidence reflects a specific regulatory mechanism rather than a core SIRT1 function. Supporting Evidence: PMID:21841822 Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination
GO:0042771 intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	IMP PMID:20100829 SIRT1 regulates autoacetylation and histone acetyltransferas...	MARK AS OVER ANNOTATED	Summary: This study links TIP60 to UV damage responses, but intrinsic apoptotic signaling is not directly demonstrated. Reason: Apoptotic pathway specificity is beyond the presented evidence. Supporting Evidence: PMID:20100829 TIP60 is autoacetylated in response to UV damage
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IMP PMID:21841822 Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-media...	KEEP AS NON CORE	Summary: SIRT1-driven FOXO3 degradation is proteasome dependent. Reason: The study demonstrates a proteasome-dependent outcome for FOXO3 turnover downstream of SIRT1. Supporting Evidence: PMID:21841822 process is proteasome dependent.
GO:0071456 cellular response to hypoxia	IMP PMID:20620956 Sirtuin 1 modulates cellular responses to hypoxia by deacety...	KEEP AS NON CORE	Summary: SIRT1 modulates cellular responses to hypoxia via HIF-1alpha deacetylation. Reason: Hypoxia response is a context-specific downstream process of SIRT1 activity. Supporting Evidence: PMID:20620956 Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha.
GO:2000757 negative regulation of peptidyl-lysine acetylation	IDA PMID:20100829 SIRT1 regulates autoacetylation and histone acetyltransferas...	ACCEPT	Summary: SIRT1 deacetylates TIP60, negatively regulating lysine acetylation. Reason: Direct deacetylation supports negative regulation of lysine acetylation. Supporting Evidence: PMID:20100829 we identified SIRT1 that specifically deacetylates TIP60 and negatively regulates TIP60 activity in vivo.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:21947282 SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) prote...	KEEP AS NON CORE	Summary: SIRT1-mediated deacetylation of DNMT1 supports gene silencing. Reason: The evidence indicates transcriptional silencing via DNMT1 regulation, a downstream effect rather than a core SIRT1 function. Supporting Evidence: PMID:21947282 SIRT1-mediated deacetylation of DNMT1 is crucial for DNMT1's multiple effects in gene silencing.
GO:0006346 DNA methylation-dependent constitutive heterochromatin formation	TAS PMID:21947282 SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) prote...	MARK AS OVER ANNOTATED	Summary: The study links SIRT1 to DNMT1-mediated gene silencing but does not demonstrate constitutive heterochromatin formation. Reason: Evidence supports DNMT1 activity and gene silencing, not heterochromatin formation specifically. Supporting Evidence: PMID:21947282 SIRT1-mediated deacetylation of DNMT1 is crucial for DNMT1's multiple effects in gene silencing.
GO:0008284 positive regulation of cell population proliferation	IMP PMID:21807113 Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.	KEEP AS NON CORE	Summary: Sirt1 supports proliferation in K562 cells via c-Myc activity. Reason: Proliferation effects are context-specific downstream outcomes. Supporting Evidence: PMID:21807113 suppress cell proliferation and arrest cell cycle at G1/S phase
GO:0033558 protein lysine deacetylase activity	IDA PMID:21807113 Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.	ACCEPT	Summary: Sirt1 deacetylates c-Myc in vitro and in vivo. Reason: Direct substrate deacetylation is reported. Supporting Evidence: PMID:21807113 deacetylates c-Myc both in vitro and in vivo
GO:0043065 positive regulation of apoptotic process	IMP PMID:19047049 Hyaluronan-mediated CD44 interaction with p300 and SIRT1 reg...	KEEP AS NON CORE	Summary: SIRT1 activation in this context leads to caspase-3 activation and apoptosis. Reason: Apoptotic effects are context-specific in breast tumor cells. Supporting Evidence: PMID:19047049 lead to an activation of caspase-3
GO:0043425 bHLH transcription factor binding	IPI PMID:21807113 Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.	ACCEPT	Summary: Sirt1 physically interacts with c-Myc, a bHLH transcription factor. Reason: Direct physical interaction is reported. Supporting Evidence: PMID:21807113 Sirt1 interacts physically with the C-terminus of c-Myc
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:21807113 Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.	KEEP AS NON CORE	Summary: Sirt1 enhances c-Myc/Max transcriptional activity. Reason: Context-specific transcriptional modulation rather than a core function. Supporting Evidence: PMID:21807113 Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.
GO:0005515 protein binding	IPI PMID:21212262 MST1 promotes apoptosis through regulating Sirt1-dependent p...	REMOVE	Summary: Generic protein binding is uninformative relative to specific mechanistic interactions. Reason: The study focuses on MST1 regulation of SIRT1 activity rather than a specific binding annotation. Supporting Evidence: PMID:21212262 Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IDA PMID:21775285 The deacetylase SIRT1 promotes membrane localization and act...	ACCEPT	Summary: SIRT1 deacetylates Akt and PDK1, supporting NAD-dependent protein lysine deacetylase activity. Reason: The abstract reports deacetylation by SIRT1 that enables Akt/PDK1 activation. Supporting Evidence: PMID:21775285 Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3)
GO:0043066 negative regulation of apoptotic process	IMP PMID:21775285 The deacetylase SIRT1 promotes membrane localization and act...	KEEP AS NON CORE	Summary: Akt/PDK1 activation by SIRT1 can influence cell survival. Reason: Represents a context-specific survival signaling effect. Supporting Evidence: PMID:21775285 Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3)
GO:2000655 negative regulation of cellular response to testosterone stimulus	IMP PMID:17505061 Sirtuin 1 is required for antagonist-induced transcriptional...	KEEP AS NON CORE	Summary: SIRT1 dampens androgen-response transcription under antagonist conditions. Reason: Specific to androgen receptor signaling context. Supporting Evidence: PMID:17505061 is required for androgen antagonist-mediated transcriptional repression and growth suppression
GO:0000785 chromatin	IDA PMID:17505061 Sirtuin 1 is required for antagonist-induced transcriptional...	ACCEPT	Summary: SIRT1 is recruited to chromatin at AR-responsive promoters. Reason: Promoter-localized deacetylation supports chromatin association. Supporting Evidence: PMID:17505061 androgen receptor (AR) recruits SIRT1 and nuclear receptor corepressor to AR-responsive promoters and deacetylates histone H3 locally
GO:0060766 negative regulation of androgen receptor signaling pathway	IMP PMID:17505061 Sirtuin 1 is required for antagonist-induced transcriptional...	KEEP AS NON CORE	Summary: SIRT1 negatively regulates androgen receptor signaling under antagonist conditions. Reason: Specific signaling-context effect rather than core function. Supporting Evidence: PMID:17505061 is required for androgen antagonist-mediated transcriptional repression and growth suppression
GO:0005634 nucleus	IDA PMID:20027304 JNK1 phosphorylates SIRT1 and promotes its enzymatic activit...	ACCEPT	Summary: SIRT1 localizes to the nucleus. Reason: Direct immunostaining shows nuclear localization. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005737 cytoplasm	IDA PMID:20027304 JNK1 phosphorylates SIRT1 and promotes its enzymatic activit...	ACCEPT	Summary: SIRT1 localizes to the cytoplasm. Reason: Direct immunostaining shows cytoplasmic localization. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0051019 mitogen-activated protein kinase binding	IPI PMID:20027304 JNK1 phosphorylates SIRT1 and promotes its enzymatic activit...	ACCEPT	Summary: SIRT1 physically interacts with the MAPK JNK1. Reason: Coimmunoprecipitation demonstrates JNK1 interaction. Supporting Evidence: PMID:20027304 We identified a functional interaction between cJUN N-terminal kinase (JNK1) and SIRT1
GO:0070301 cellular response to hydrogen peroxide	IDA PMID:20027304 JNK1 phosphorylates SIRT1 and promotes its enzymatic activit...	KEEP AS NON CORE	Summary: SIRT1 responds to oxidative stress by changing nuclear localization. Reason: Stress-responsive localization is a context-specific regulatory effect. Supporting Evidence: PMID:20027304 Treatment with H2O2 increased nuclear localization of SIRT1
GO:0018394 peptidyl-lysine acetylation	IMP PMID:18004385 SIRT1 regulates the histone methyl-transferase SUV39H1 durin...	REMOVE	Summary: SIRT1 deacetylates SUV39H1; this is deacetylation rather than acetylation. Reason: The evidence supports deacetylation activity, not acetylation. Supporting Evidence: PMID:18004385 SIRT1 interacts directly with, recruits and deacetylates SUV39H1
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re...	KEEP AS NON CORE	Summary: SIRT1 contributes to transcriptional repression mediated by HES1/HEY2. Reason: Context-specific repression via bHLH factors. Supporting Evidence: PMID:12535671 SIRT1-dependent and -independent deacetylase pathways are involved in the transcriptional repressions
GO:0003714 transcription corepressor activity	IDA PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re...	ACCEPT	Summary: SIRT1 functions as a transcriptional corepressor with HES1/HEY2. Reason: Corepressor activity is directly supported. Supporting Evidence: PMID:12535671 SIRT1-dependent and -independent deacetylase pathways are involved in the transcriptional repressions
GO:0043398 HLH domain binding	IPI PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re...	ACCEPT	Summary: SIRT1 associates with HLH/bHLH repressors HES1 and HEY2. Reason: Physical association with bHLH proteins is reported. Supporting Evidence: PMID:12535671 SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2
GO:0043425 bHLH transcription factor binding	IPI PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re...	ACCEPT	Summary: SIRT1 binds bHLH transcription factors HES1 and HEY2. Reason: Direct interaction with bHLH factors is reported. Supporting Evidence: PMID:12535671 SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2
GO:0000791 euchromatin	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	KEEP AS NON CORE	Summary: SIRT1 was targeted to a reporter integrated in euchromatin in this study. Reason: Represents context-specific targeting rather than core localization. Supporting Evidence: PMID:15469825 a Gal4-reporter integrated in euchromatin
GO:0000792 heterochromatin	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: SIRT1 promotes heterochromatin formation via histone deacetylation. Reason: Core chromatin silencing function in this reference. Supporting Evidence: PMID:15469825 SirT1-mediated heterochromatin formation that includes deacetylation of histone tails
GO:0005637 nuclear inner membrane	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: Nuclear inner membrane localization is supported by broader SIRT1 localization evidence. Reason: Consistent with curated localization annotations for SIRT1. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0046969 histone H3K9 deacetylase activity, NAD-dependent	ISS GO_REF:0000024	ACCEPT	Summary: SIRT1 deacetylates histone H3K9 as part of its core activity. Reason: Supported by multiple SIRT1 histone deacetylase studies.
GO:0005634 nucleus	IDA PMID:19934257 SIRT1 deacetylates APE1 and regulates cellular base excision...	ACCEPT	Summary: SIRT1 is nuclear in studies of APE1 regulation. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0032071 regulation of endodeoxyribonuclease activity	IMP PMID:19934257 SIRT1 deacetylates APE1 and regulates cellular base excision...	ACCEPT	Summary: SIRT1 deacetylates APE1, modulating its endonuclease activity. Reason: APE1 is a direct SIRT1 substrate in base excision repair. Supporting Evidence: PMID:19934257 SIRT1 deacetylates APE1 in vitro and in vivo targeting lysines 6 and 7
GO:0033558 protein lysine deacetylase activity	IDA PMID:19934257 SIRT1 deacetylates APE1 and regulates cellular base excision...	ACCEPT	Summary: APE1 is a target of the SIRT1 protein deacetylase. Reason: Direct substrate deacetylation supports this activity. Supporting Evidence: PMID:19934257 APE1 is a target of the SIRTUIN1 (SIRT1) protein deacetylase
GO:0045739 positive regulation of DNA repair	IMP PMID:19934257 SIRT1 deacetylates APE1 and regulates cellular base excision...	ACCEPT	Summary: SIRT1 promotes base excision repair and genomic integrity. Reason: Evidence supports a positive role in DNA repair pathways. Supporting Evidence: PMID:19934257 SIRT1 plays a vital role in maintaining genomic integrity through regulation of the BER pathway
GO:0006476 protein deacetylation	IDA PMID:20027304 JNK1 phosphorylates SIRT1 and promotes its enzymatic activit...	ACCEPT	Summary: SIRT1 catalyzes protein deacetylation. Reason: Core biochemical process of SIRT1 activity. Supporting Evidence: PMID:20027304 SIRT1 is a NAD-dependent deacetylase that regulates a variety of pathways
GO:0000183 rDNA heterochromatin formation	IDA PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	ACCEPT	Summary: eNoSC containing SIRT1 establishes silent chromatin at rDNA loci. Reason: Supported by the eNoSC complex and rDNA chromatin silencing. Supporting Evidence: PMID:18485871 eNoSC contains Nucleomethylin, which binds histone H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1 and SUV39H1. PMID:18485871 thus establishing silent chromatin in the rDNA locus.
GO:0005677 chromatin silencing complex	IDA PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	ACCEPT	Summary: SIRT1 is part of the eNoSC chromatin silencing complex. Reason: Complex membership is explicitly described. Supporting Evidence: PMID:18485871 eNoSC contains Nucleomethylin, which binds histone H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1 and SUV39H1.
GO:0033553 rDNA heterochromatin	IDA PMID:18485871 Epigenetic control of rDNA loci in response to intracellular...	ACCEPT	Summary: Silent chromatin is established at rDNA loci by eNoSC. Reason: Supports rDNA heterochromatin at the locus. Supporting Evidence: PMID:18485871 thus establishing silent chromatin in the rDNA locus.
GO:0005654 nucleoplasm	IDA PMID:16079181 Evolutionarily conserved and nonconserved cellular localizat...	ACCEPT	Summary: SIRT1 is among the nuclear sirtuins with distinct subnuclear localizations. Reason: The study identifies SIRT1 as a nuclear SIRT protein. Supporting Evidence: PMID:16079181 three nuclear SIRT proteins (SIRT1, SIRT6, and SIRT7) show different subnuclear localizations
GO:0005730 nucleolus	IDA NOT PMID:16079181 Evolutionarily conserved and nonconserved cellular localizat...	KEEP AS NON CORE	Summary: SIRT1 is not reported as nucleolar in this study. Reason: Subnuclear localization is context-specific; NOT annotation kept as non-core. Supporting Evidence: PMID:16079181 2005 Aug 3. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins.
GO:0005515 protein binding	IPI PMID:17172643 Multiple histone deacetylases and the CREB-binding protein r...	REMOVE	Summary: Generic protein binding is uninformative in this context. Reason: The study focuses on deacetylation by multiple HDACs rather than a specific binding interaction. Supporting Evidence: PMID:17172643 HDAC1, HDAC3, HDAC10, SIRT1, and SIRT2 were involved in in vivo deacetylation.
GO:0003714 transcription corepressor activity	ISS GO_REF:0000024	ACCEPT	Summary: SIRT1 functions as a transcriptional corepressor in multiple contexts. Reason: Supported by multiple experimental studies of SIRT1 corepressor roles.
GO:0006642 triglyceride mobilization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 can influence triglyceride mobilization through deacetylation of metabolic regulators. Reason: Downstream metabolic regulation rather than a core function.
GO:0009267 cellular response to starvation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 responds to nutrient status via NAD+-dependent deacetylase activity and influences starvation responses. Reason: Downstream metabolic response rather than a core function.
GO:0031507 heterochromatin formation	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: SirT1-mediated deacetylation supports heterochromatin formation. Reason: Core chromatin silencing activity in this study. Supporting Evidence: PMID:15469825 SirT1-mediated heterochromatin formation that includes deacetylation of histone tails
GO:0042393 histone binding	IPI PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: SIRT1 interacts with histone H1. Reason: Histone interaction is part of the core chromatin regulation mechanism. Supporting Evidence: PMID:15469825 SirT1 interacts with and deacetylates histone H1 at lysine 26.
GO:0042802 identical protein binding	IPI PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	UNDECIDED	Summary: Identical protein binding is not described in the PMID:15469825 abstract. Reason: Need direct evidence for homomeric binding. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0045599 negative regulation of fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences fat cell differentiation. Reason: Downstream metabolic regulation rather than a core function.
GO:0050872 white fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SIRT1 influences white fat cell differentiation. Reason: Downstream metabolic regulation rather than a core function.
GO:0002039 p53 binding	IPI PMID:11672523 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.	ACCEPT	Summary: SIRT1 binds p53 as a deacetylation substrate. Reason: Direct p53 binding is reported. Supporting Evidence: PMID:11672523 binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue
GO:0003950 NAD+ poly-ADP-ribosyltransferase activity	TAS NOT PMID:17456799 Sirtuin functions in health and disease.	UNDECIDED	Summary: Review notes that some sirtuins have ADP-ribosyltransferase activity but does not specify SIRT1. Reason: The reference does not provide SIRT1-specific evidence to support or refute this activity. Supporting Evidence: PMID:17456799 Certain sirtuins have in addition an ADP-ribosyltransferase activity.
GO:0005634 nucleus	IDA PMID:11672523 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.	ACCEPT	Summary: SIRT1 is nuclear in cells where p53 deacetylation occurs. Reason: Consistent with nuclear localization in SIRT1 studies. Supporting Evidence: PMID:20027304 SIRT1 was localized both in cytoplasmic and nuclear compartments
GO:0005635 nuclear envelope	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	UNDECIDED	Summary: Nuclear envelope localization is not described in the PMID:15469825 abstract. Reason: Insufficient evidence in this reference for nuclear envelope localization. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0005730 nucleolus	IDA PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	KEEP AS NON CORE	Summary: Nucleolar localization is context-specific and not central to SIRT1 function. Reason: Subnuclear localization is a downstream/context-specific aspect. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0005737 cytoplasm	IDA NOT PMID:15469825 Human SirT1 interacts with histone H1 and promotes formation...	ACCEPT	Summary: This study does not report cytoplasmic localization; the NOT annotation is acceptable. Reason: Consistent with the lack of cytoplasmic localization evidence in this reference. Supporting Evidence: PMID:15469825 SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro.
GO:0016605 PML body	IDA PMID:12006491 Human SIR2 deacetylates p53 and antagonizes PML/p53-induced ...	ACCEPT	Summary: SIRT1 localizes to PML nuclear bodies. Reason: Direct localization to PML bodies is reported. Supporting Evidence: PMID:12006491 SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies
GO:0042127 regulation of cell population proliferation	IMP PMID:12006491 Human SIR2 deacetylates p53 and antagonizes PML/p53-induced ...	KEEP AS NON CORE	Summary: SIRT1 rescues PML-induced premature senescence, indicating effects on cell proliferation state. Reason: Senescence modulation is downstream and context-specific. Supporting Evidence: PMID:12006491 rescues PML-mediated premature cellular senescence
GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator	IDA PMID:11672523 hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.	KEEP AS NON CORE	Summary: SIRT1 modulates p53-mediated DNA damage responses via deacetylation. Reason: Downstream consequence of p53 regulation rather than core function. Supporting Evidence: PMID:11672523 binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue
GO:0006476 protein deacetylation	IDA PMID:18203716 Regulation of WRN protein cellular localization and enzymati...	ACCEPT	Summary: SIRT1 deacetylates protein substrates such as WRN. Reason: Direct deacetylation activity is reported. Supporting Evidence: PMID:18203716 SIRT1 can deacetylate WRN both in vitro and in vivo.
GO:0006974 DNA damage response	IDA PMID:18203716 Regulation of WRN protein cellular localization and enzymati...	ACCEPT	Summary: SIRT1 regulates WRN-mediated responses to DNA damage. Reason: DNA damage response is a supported functional role for SIRT1. Supporting Evidence: PMID:18203716 SIRT1 regulates WRN-mediated cellular responses to DNA damage through deacetylation of WRN.
GO:0019213 deacetylase activity	IDA PMID:18203716 Regulation of WRN protein cellular localization and enzymati...	ACCEPT	Summary: SIRT1 deacetylates WRN. Reason: Deacetylase activity is supported by direct substrate deacetylation. Supporting Evidence: PMID:18203716 SIRT1 can deacetylate WRN both in vitro and in vivo.
GO:0017136 histone deacetylase activity, NAD-dependent	IDA PMID:16959573 SIRT4 inhibits glutamate dehydrogenase and opposes the effec...	ACCEPT	Summary: Core NAD-dependent histone deacetylase activity demonstrated experimentally. Reason: Core molecular function. SIRT1 is a well-established NAD-dependent histone deacetylase. Supporting Evidence: PMID:16959573 SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.

Core Functions

Primary enzymatic function of SIRT1. Catalyzes NAD-dependent removal of acetyl groups from lysine residues of histones and numerous non-histone proteins. The reaction couples NAD+ cleavage to lysine deacetylation, producing nicotinamide and 2-O-acetyl-ADP-ribose.

Molecular Function:

NAD-dependent protein lysine deacetylase activity

Preferential histone substrate. Deacetylation of H4K16 is a major activity of SIRT1 critical for heterochromatin formation and transcriptional silencing.

Molecular Function:

histone H4K16 deacetylase activity, NAD-dependent

Major histone substrate. H3K9 deacetylation is linked to heterochromatin formation at rDNA and telomeric regions.

Molecular Function:

histone H3K9 deacetylase activity, NAD-dependent

SIRT1 functions as a transcriptional corepressor through histone deacetylation and deacetylation of transcription factors.

Molecular Function:

transcription corepressor activity

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11672522

Negative control of p53 by Sir2alpha promotes cell survival under stress.

PMID:11672523

hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.

PMID:12006491

Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence.

PMID:12535671

Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression.

PMID:12837246

Multiple tumor suppressor pathways negatively regulate telomerase.

PMID:14976264

Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.

PMID:15126506

FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).

PMID:15152190

Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.

PMID:15175761

Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.

PMID:15205477

Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.

PMID:15220471

Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.

PMID:15469825

Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin.

PMID:15632193

SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1.

PMID:15684044

Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation.

PMID:15692560

Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation.

PMID:16079181

Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins.

PMID:16892051

Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage.

PMID:16959573

SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.

PMID:16998810

SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity.

PMID:17172643

Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing.

PMID:17317627

Phosphorylation of HuR by Chk2 regulates SIRT1 expression.

PMID:17334224

SIRT1 promotes DNA repair activity and deacetylation of Ku70.

PMID:17456799

Sirtuin functions in health and disease.

PMID:17505061

Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor.

PMID:17612497

SIRT1 regulates the function of the Nijmegen breakage syndrome protein.

PMID:17680780

Sirt1 interacts with transducin-like enhancer of split-1 to inhibit nuclear factor kappaB-mediated transcription.

PMID:17901049

The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation.

PMID:17916362

Sirt1 modulates premature senescence-like phenotype in human endothelial cells.

PMID:17936707

SIRT1 deacetylates and positively regulates the nuclear receptor LXR.

PMID:17964266

Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity.

PMID:18004385

SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation.

PMID:18203716

Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation.

PMID:18235501

DBC1 is a negative regulator of SIRT1.

PMID:18235502

Negative regulation of the deacetylase SIRT1 by DBC1.

PMID:18296641

A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy.

PMID:18485871

Epigenetic control of rDNA loci in response to intracellular energy status.

PMID:18662546

SIRT1 regulates circadian clock gene expression through PER2 deacetylation.

PMID:18687677

SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation.

PMID:19047049

Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells.

PMID:19188449

hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in response to DNA damage.

PMID:19236849

Carboxy-terminal phosphorylation of SIRT1 by protein kinase CK2.

PMID:19343720

Identification and characterization of proteins interacting with SIRT1 and SIRT3: implications in the anti-aging and metabolic effects of sirtuins.

PMID:19478080

Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters.

PMID:19680552

CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA-damage.

PMID:19690166

Transcriptional corepressor SMILE recruits SIRT1 to inhibit nuclear receptor estrogen receptor-related receptor gamma transactivation.

PMID:19934257

SIRT1 deacetylates APE1 and regulates cellular base excision repair.

PMID:19934264

Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells.

PMID:20027304

JNK1 phosphorylates SIRT1 and promotes its enzymatic activity.

PMID:20074560

Repression of estrogen receptor beta function by putative tumor suppressor DBC1.

PMID:20097625

Role of SIRT1 in homologous recombination.

PMID:20100829

SIRT1 regulates autoacetylation and histone acetyltransferase activity of TIP60.

PMID:20167603

DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1.

PMID:20169165

SIRT1 negatively regulates the mammalian target of rapamycin.

PMID:20203304

SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells.

PMID:20375098

Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation.

PMID:20424141

MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1.

PMID:20439735

SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling.

PMID:20620956

Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha.

PMID:20660480

SIRT1 is regulated by a PPAR{γ}-SIRT1 negative feedback loop associated with senescence.

PMID:20670893

SIRT1 regulates UV-induced DNA repair through deacetylating XPA.

PMID:20817729

SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism.

PMID:20955178

Regulation of unfolded protein response modulator XBP1s by acetylation and deacetylation.

PMID:21030595

HDAC3 is negatively regulated by the nuclear protein DBC1.

PMID:21081649

SIRT2 regulates NF-κB dependent gene expression through deacetylation of p65 Lys310.

PMID:21149730

Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C.

PMID:21212262

MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation.

PMID:21241768

Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1.

PMID:21245319

Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1).

PMID:21471201

Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1.

PMID:21555002

EVI1 up-regulates the stress responsive gene SIRT1 which triggers deacetylation and degradation of EVI1.

PMID:21698133

SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.

PMID:21775285

The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.

PMID:21807113

Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.

PMID:21841822

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation.

PMID:21890893

SIRT1 links CIITA deacetylation to MHC II activation.

PMID:21909281

The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.

PMID:21947282

SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.

PMID:21968188

p53 deacetylation by SIRT1 decreases during protein kinase CKII downregulation-mediated cellular senescence.

PMID:22094255

Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands.

PMID:22169038

SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive.

PMID:22190034

Global landscape of HIV-human protein complexes.

PMID:22510882

Novel repressor regulates insulin sensitivity through interaction with Foxo1.

PMID:22863012

Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ.

PMID:22918831

Autoacetylation of the MYST lysine acetyltransferase MOF protein.

PMID:22956909

Dynamic distribution of linker histone H1.5 in cellular differentiation.

PMID:23056314

Angiogenesis inhibitor vasohibin-1 enhances stress resistance of endothelial cells via induction of SOD2 and SIRT1.

PMID:23142079

The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis.

PMID:23382074

A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.

PMID:23960241

MicroRNA-mediated epigenetic silencing of sirtuin1 contributes to impaired angiogenic responses.

PMID:24043310

SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation.

PMID:24048733

Antidicer RNAse activity of monocyte chemotactic protein-induced protein-1 is critical for inducing angiogenesis.

PMID:24681097

AROS has a context-dependent effect on SIRT1.

PMID:24824780

MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm.

PMID:25217442

Vascular importance of the miR-212/132 cluster.

PMID:25661920

CCAR2 negatively regulates nuclear receptor LXRα by competing with SIRT1 deacetylase.

PMID:25751424

NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1.

PMID:28497810

Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29656858

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

PMID:29681526

A Designed Peptide Targets Two Types of Modifications of p53 with Anti-cancer Activity.

PMID:29765047

Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate.

PMID:30193097

Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Toggles Enzyme Activity between Gluconeogenic and Anaplerotic Reactions.

PMID:30409912

Dynamic acetylation of the kinetochore-associated protein HEC1 ensures accurate microtubule-kinetochore attachment.

PMID:31403225

The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification.

PMID:31722219

CCDC84 Acetylation Oscillation Regulates Centrosome Duplication by Modulating HsSAS-6 Degradation.

PMID:32034146

Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and activation.

PMID:32538779

Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice.

PMID:32761762

CSAG2 is a cancer-specific activator of SIRT1.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:38512451

The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer.

Reactome:R-HSA-3371453

Regulation of HSF1-mediated heat shock response

Reactome:R-HSA-3371467

SIRT1 deacetylates HSF1

Reactome:R-HSA-3371518

SIRT1 binds to HSF1

Reactome:R-HSA-3371537

DBC1 binds SIRT1

Reactome:R-HSA-427359

SIRT1 negatively regulates rRNA expression

Reactome:R-HSA-427514

eNoSC deacetylates histone H3

Reactome:R-HSA-427527

eNoSC dimethylates histone H3 at lysine-9

Reactome:R-HSA-427528

Formation of energy-dependent Nucleolar Silencing Complex (eNoSC)

Reactome:R-HSA-9620532

SIRT1,SIRT3 deacetylate FOXO3

Reactome:R-HSA-9765850

ZEB1 recruits MPHOSPH8 (MPP8) to CDH1 gene promoter

Reactome:R-HSA-9825772

SIRT1 deacetylates HINT1 dimer

Reactome:R-HSA-9854916

MITF-M-dependent SIRT1 gene expression

file:human/SIRT1/SIRT1-deep-research-falcon.md

Deep research report on SIRT1

📚 Additional Documentation

Deep Research Bioreason

(SIRT1-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:49 AM

Organism: Homo sapiens

Sequence:

MADEAALALQPGGSPSAAGADREAASSPAGEPLRKRPRRDGPGLERSPGEPGGAAPEREVPAAARGCPGAAAAALWREAEAEAAAAGGEQEAQATAAAGEGDNGPGLQGPSREPPLADNLYDEDDDDEGEEEEEAAAAAIGYRDNLLFGDEIITNGFHSCESDEEDRASHASSSDWTPRPRIGPYTFVQQHLMIGTDPRTILKDLLPETIPPPELDDMTLWQIVINILSEPPKRKKRKDINTIEDAVKLLQECKKIIVLTGAGVSVSCGIPDFRSRDGIYARLAVDFPDLPDPQAMFDIEYFRKDPRPFFKFAKEIYPGQFQPSLCHKFIALSDKEGKLLRNYTQNIDTLEQVAGIQRIIQCHGSFATASCLICKYKVDCEAVRGDIFNQVVPRCPRCPADEPLAIMKPEIVFFGENLPEQFHRAMKYDKDEVDLLIVIGSSLKVRPVALIPSSIPHEVPQILINREPLPHLHFDVELLGDCDVIINELCHRLGGEYAKLCCNPVKLSEITEKPPRTQKELAYLSELPPTPLHVSEDSSSPERTSPPDSSVIVTLLDQAAKSNDDLDVSESKGCMEEKPQEVQTSRNVESIAEQMENPDLKNVGSSTGEKNERTSVAGTVRKCWPNRVAKEQISRRLDGNQYLFLPPNRYIFHGAEVYSDSEDDVLSSSSCGSNSDSGTCQSPSLEEPMEDESEIEEFYNGLEDEPDVPERAGGAGFGTDGDDQEAINEAISVKQEVTDMNYPSNKS

Thinking Trace

I begin by dissecting the InterPro architecture and its order along the polypeptide. A large central block from residues 229–508 is annotated as IPR029035 (DHS-like NAD/FAD-binding domain superfamily), indicating a Rossmann-like fold that binds nicotinamide adenine dinucleotide and supports oxidative deacylation chemistry. Nested within this region, residues 235–506 carry IPR050134 (NAD-dependent sirtuin protein deacylases family), and residues 236–496 define IPR026590 (Sirtuin family, catalytic core domain). This catalytic core is further supported by IPR003000 (Sirtuin family) spanning residues 261–447 and by IPR026591 (Sirtuin, catalytic core small domain superfamily) across residues 267–419. The layered overlap of these five sirtuin signatures establishes a canonical class III lysine deacylase architecture: an NAD-dependent catalytic center that couples acyl-lysine cleavage to NAD+ consumption and product formation. The positional coherence—broad NAD-binding superfamily enveloping a tightly conserved sirtuin catalytic core—causally dictates an enzymatic molecular function that requires NAD+ and acts on acylated lysines.

From this catalytic architecture, the molecular function resolves to NAD-dependent protein deacylase chemistry. The sirtuin core (IPR026590/IPR026591) enforces NAD-coupled hydrolysis of acyl modifications on lysine side chains. This mechanism explains the formal molecular function label GO:0005515 and, mechanistically, it is the chemistry that underlies removal of acyl groups from histones and other proteins. The presence of multiple sirtuin family signatures (IPR003000; IPR050134) argues that the enzyme acts not only as a deacylase but can, depending on its active-site environment and substrate channeling, also support auxiliary acyltransferase or isomerase reactions—behavior frequently observed across sirtuin-like enzymes.

The biological process follows from the chemistry and known substrate classes. By reversing lysine acylation states, sirtuin cores remodel chromatin and tune transcriptional circuits, apoptosis pathways, and stress responses. This deacylation control directly feeds into chromatin regulation and transcriptional modulation; it also modulates mitochondrial function and apoptotic checkpoints through changes in mitochondrial proteome and chromatin-linked signaling. Thus, the enzymatic profile drives higher-order processes best captured as broad regulatory pathways in gene expression and cell fate decisions.

Cellular localization is inferred from the soluble, non-membranous architecture of sirtuin cores and their roles. The absence of transmembrane segments and the soluble NAD-binding fold point to a cytoplasmic and nuclear distribution. Sirtuin-mediated chromatin and transcriptional control requires nuclear access, while cytoplasmic and mitochondrial substrate pools require cytoplasmic presence. Consequently, a soluble localization in the cytoplasm and nucleus is expected.

Integrating these layers yields a mechanistic hypothesis: the enzyme binds NAD+ via its DHS-like fold and sirtuin catalytic core to execute NAD-dependent deacylation of acylated lysines. This chemistry resets protein and histone acylation states, thereby reprogramming transcriptional and apoptotic pathways. It likely shuttles between nucleus and cytoplasm, engaging chromatin-associated complexes and cytoplasmic acylated substrates. Expected interaction partners include chromatin-modifying assemblies and transcriptional regulators that present acylated lysines; acyltransferases that establish the modification landscape the enzyme reverses; and mitochondrial or cytosolic protein complexes whose function depends on lysine acylation cycles.

Functional Summary

A soluble human NAD-dependent lysine deacylase that uses a sirtuin catalytic core to reverse acylation marks on proteins and histones, thereby tuning chromatin state, transcriptional programs, and cell-fate pathways. Its soluble fold and regulatory role indicate distribution between cytoplasm and nucleus, where it binds nicotinamide adenine cofactors to drive deacylation chemistry and modulate apoptotic and stress-responsive networks through dynamic control of lysine acylation.

UniProt Summary

NAD-dependent protein deacylase. Acts as a lysine deacetylase, catalyzing the NAD-dependent hydrolysis of acetylated lysine residues (By similarity).

InterPro Domains

DHS-like NAD/FAD-binding domain superfamily (IPR029035, homologous_superfamily) — residues 229-508
NAD-dependent sirtuin protein deacylases (IPR050134, family) — residues 235-506
Sirtuin family, catalytic core domain (IPR026590, domain) — residues 236-496
Sirtuin family (IPR003000, family) — residues 261-447
Sirtuin, catalytic core small domain superfamily (IPR026591, homologous_superfamily) — residues 267-419

GO Terms

Molecular Function: molecular_function (GO:0003674), catalytic activity (GO:0003824), binding (GO:0005488), transcription regulator activity (GO:0140110), protein binding (GO:0005515), transferase activity (GO:0016740), hydrolase activity (GO:0016787), protein-containing complex binding (GO:0044877), catalytic activity, acting on a protein (GO:0140096), transcription coregulator activity (GO:0003712), transcription factor binding (GO:0008134), histone binding (GO:0042393), p53 binding (GO:0002039), identical protein binding (GO:0042802), protein lysine deacetylase activity (GO:0033558), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds (GO:0016810), transcription corepressor activity (GO:0003714), acyltransferase activity (GO:0016746), protein domain specific binding (GO:0019904), enzyme binding (GO:0019899), deacetylase activity (GO:0019213), histone deacetylase activity (GO:0004407), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747), NAD-dependent protein deacetylase activity (GO:0034979), kinase binding (GO:0019900), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811), DNA-binding transcription factor binding (GO:0140297), bHLH transcription factor binding (GO:0043425), NAD-dependent histone deacetylase activity (GO:0017136), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein kinase binding (GO:0019901), mitogen-activated protein kinase binding (GO:0051019), nuclear receptor binding (GO:0016922)

Biological Process: biological_process (GO:0008150), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), negative regulation of biological process (GO:0048519), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), multicellular organismal process (GO:0032501), rhythmic process (GO:0048511), developmental process (GO:0032502), cellular process (GO:0009987), metabolic process (GO:0008152), homeostatic process (GO:0042592), anatomical structure development (GO:0048856), negative regulation of signaling (GO:0023057), positive regulation of multicellular organismal process (GO:0051240), positive regulation of immune system process (GO:0002684), cellular component organization or biogenesis (GO:0071840), regulation of multicellular organismal process (GO:0051239), multicellular organismal-level homeostasis (GO:0048871), anatomical structure formation involved in morphogenesis (GO:0048646), negative regulation of metabolic process (GO:0009892), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), negative regulation of cellular process (GO:0048523), regulation of locomotion (GO:0040012), response to abiotic stimulus (GO:0009628), regulation of metabolic process (GO:0019222), positive regulation of response to stimulus (GO:0048584), catabolic process (GO:0009056), regulation of molecular function (GO:0065009), cell communication (GO:0007154), positive regulation of cellular process (GO:0048522), response to external stimulus (GO:0009605), anatomical structure morphogenesis (GO:0009653), response to chemical (GO:0042221), nitrogen compound metabolic process (GO:0006807), regulation of developmental process (GO:0050793), response to endogenous stimulus (GO:0009719), cell death (GO:0008219), positive regulation of locomotion (GO:0040017), regulation of signaling (GO:0023051), signal transduction (GO:0007165), positive regulation of signaling (GO:0023056), multicellular organism development (GO:0007275), circadian rhythm (GO:0007623), regulation of immune system process (GO:0002682), organic substance metabolic process (GO:0071704), cellular metabolic process (GO:0044237), positive regulation of metabolic process (GO:0009893), response to stress (GO:0006950), negative regulation of growth (GO:0045926), positive regulation of developmental process (GO:0051094), negative regulation of response to stimulus (GO:0048585), regulation of growth (GO:0040008), primary metabolic process (GO:0044238), regulation of cell motility (GO:2000145), response to radiation (GO:0009314), regulation of response to stress (GO:0080134), regulation of signal transduction (GO:0009966), regulation of macromolecule metabolic process (GO:0060255), cellular aromatic compound metabolic process (GO:0006725), regulation of epithelial cell migration (GO:0010632), negative regulation of response to DNA damage stimulus (GO:2001021), response to inorganic substance (GO:0010035), positive regulation of vasculature development (GO:1904018), negative regulation of macromolecule metabolic process (GO:0010605), cellular senescence (GO:0090398), regulation of anatomical structure morphogenesis (GO:0022603), negative regulation of cell cycle (GO:0045786), cellular response to extracellular stimulus (GO:0031668), cellular macromolecule metabolic process (GO:0044260), regulation of cell cycle process (GO:0010564), positive regulation of nitrogen compound metabolic process (GO:0051173), regulation of catalytic activity (GO:0050790), negative regulation of nitrogen compound metabolic process (GO:0051172), positive regulation of molecular function (GO:0044093), positive regulation of macromolecule metabolic process (GO:0010604), blood vessel development (GO:0001568), energy homeostasis (GO:0097009), heterocycle metabolic process (GO:0046483), negative regulation of molecular function (GO:0044092), protein metabolic process (GO:0019538), regulation of cell growth (GO:0001558), regulation of cellular response to stress (GO:0080135), response to oxygen-containing compound (GO:1901700), cellular nitrogen compound metabolic process (GO:0034641), macromolecule metabolic process (GO:0043170), positive regulation of cell motility (GO:2000147), positive regulation of biosynthetic process (GO:0009891), regulation of ATP-dependent activity (GO:0043462), angiogenesis (GO:0001525), positive regulation of response to DNA damage stimulus (GO:2001022), regulation of multicellular organismal development (GO:2000026), cellular response to environmental stimulus (GO:0104004), regulation of immune response (GO:0050776), regulation of cell population proliferation (GO:0042127), regulation of cell death (GO:0010941), response to starvation (GO:0042594), positive regulation of cellular metabolic process (GO:0031325), cellular response to stress (GO:0033554), regulation of DNA-binding transcription factor activity (GO:0051090), regulation of cellular metabolic process (GO:0031323), negative regulation of biosynthetic process (GO:0009890), positive regulation of cell communication (GO:0010647), regulation of primary metabolic process (GO:0080090), circadian regulation of gene expression (GO:0032922), response to hypoxia (GO:0001666), negative regulation of signal transduction (GO:0009968), positive regulation of cell death (GO:0010942), programmed cell death (GO:0012501), negative regulation of cell death (GO:0060548), positive regulation of cellular response to insulin stimulus (GO:1900078), cellular catabolic process (GO:0044248), system development (GO:0048731), response to oxygen levels (GO:0070482), response to growth factor (GO:0070848), cellular response to endogenous stimulus (GO:0071495), regulation of microtubule-based process (GO:0032886), tube development (GO:0035295), regulation of cell cycle (GO:0051726), regulation of catabolic process (GO:0009894), organic cyclic compound metabolic process (GO:1901360), cellular response to abiotic stimulus (GO:0071214), apoptotic signaling pathway (GO:0097190), negative regulation of cell growth (GO:0030308), regulation of nitrogen compound metabolic process (GO:0051171), positive regulation of immune response (GO:0050778), cell surface receptor signaling pathway (GO:0007166), cellular component organization (GO:0016043), regulation of cellular component organization (GO:0051128), organic substance catabolic process (GO:1901575), cellular response to external stimulus (GO:0071496), positive regulation of cell population proliferation (GO:0008284), tube morphogenesis (GO:0035239), positive regulation of signal transduction (GO:0009967), negative regulation of cell communication (GO:0010648), organonitrogen compound metabolic process (GO:1901564), positive regulation of carbohydrate metabolic process (GO:0045913), intracellular signal transduction (GO:0035556), response to oxidative stress (GO:0006979), negative regulation of cellular metabolic process (GO:0031324), response to organic substance (GO:0010033), response to extracellular stimulus (GO:0009991), positive regulation of small molecule metabolic process (GO:0062013), regulation of cellular response to insulin stimulus (GO:1900076), nucleobase-containing compound metabolic process (GO:0006139), regulation of cell communication (GO:0010646), cellular response to chemical stimulus (GO:0070887), regulation of biosynthetic process (GO:0009889), regulation of small molecule metabolic process (GO:0062012), positive regulation of catabolic process (GO:0009896), regulation of intracellular steroid hormone receptor signaling pathway (GO:0033143), regulation of macromolecule biosynthetic process (GO:0010556), cellular response to oxygen levels (GO:0071453), regulation of protein metabolic process (GO:0051246), vasculature development (GO:0001944), negative regulation of intracellular steroid hormone receptor signaling pathway (GO:0033144), regulation of cellular carbohydrate metabolic process (GO:0010675), regulation of helicase activity (GO:0051095), regulation of epithelial cell proliferation (GO:0050678), regulation of gene expression (GO:0010468), regulation of cellular response to oxidative stress (GO:1900407), macromolecule modification (GO:0043412), regulation of endothelial cell migration (GO:0010594), regulation of oxidative stress-induced cell death (GO:1903201), positive regulation of autophagy (GO:0010508), circulatory system development (GO:0072359), response to decreased oxygen levels (GO:0036293), regulation of response to oxidative stress (GO:1902882), negative regulation of phosphorus metabolic process (GO:0010563), positive regulation of cell migration (GO:0030335), intrinsic apoptotic signaling pathway (GO:0097193), regulation of centrosome cycle (GO:0046605), positive regulation of catalytic activity (GO:0043085), cellular response to oxygen-containing compound (GO:1901701), negative regulation of gene expression (GO:0010629), cellular response to radiation (GO:0071478), cellular response to hypoxia (GO:0071456), response to transforming growth factor beta (GO:0071559), response to light stimulus (GO:0009416), regulation of carbohydrate biosynthetic process (GO:0043255), enzyme-linked receptor protein signaling pathway (GO:0007167), organonitrogen compound catabolic process (GO:1901565), proteolysis (GO:0006508), cellular response to DNA damage stimulus (GO:0006974), cellular response to organic substance (GO:0071310), regulation of DNA metabolic process (GO:0051052), cellular response to chemical stress (GO:0062197), negative regulation of protein metabolic process (GO:0051248), negative regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043518), regulation of vasculature development (GO:1901342), positive regulation of insulin receptor signaling pathway (GO:0046628), positive regulation of angiogenesis (GO:0045766), regulation of glucose metabolic process (GO:0010906), regulation of autophagy (GO:0010506), chromatin organization (GO:0006325), negative regulation of apoptotic signaling pathway (GO:2001234), regulation of response to DNA damage stimulus (GO:2001020), negative regulation of cellular senescence (GO:2000773), positive regulation of epithelial cell proliferation (GO:0050679), protein modification process (GO:0036211), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of RNA metabolic process (GO:0051254), positive regulation of glucose metabolic process (GO:0010907), cellular macromolecule catabolic process (GO:0044265), positive regulation of histone methylation (GO:0031062), regulation of cellular biosynthetic process (GO:0031326), apoptotic process (GO:0006915), regulation of nucleobase-containing compound metabolic process (GO:0019219), regulation of angiogenesis (GO:0045765), response to hydrogen peroxide (GO:0042542), regulation of transferase activity (GO:0051338), regulation of nuclease activity (GO:0032069), cellular response to nutrient levels (GO:0031669), negative regulation of ATP-dependent activity (GO:0032780), positive regulation of cellular biosynthetic process (GO:0031328), cellular response to growth factor stimulus (GO:0071363), response to reactive oxygen species (GO:0000302), cellular response to oxidative stress (GO:0034599), regulation of mitotic cell cycle (GO:0007346), regulation of cellular senescence (GO:2000772), negative regulation of programmed cell death (GO:0043069), regulation of programmed cell death (GO:0043067), protein catabolic process (GO:0030163), signal transduction by p53 class mediator (GO:0072331), regulation of cell migration (GO:0030334), macromolecule catabolic process (GO:0009057), nucleic acid metabolic process (GO:0090304), response to nutrient levels (GO:0031667), DNA metabolic process (GO:0006259), negative regulation of cellular biosynthetic process (GO:0031327), regulation of RNA metabolic process (GO:0051252), regulation of centrosome duplication (GO:0010824), negative regulation of nucleobase-containing compound metabolic process (GO:0045934), regulation of adaptive immune response (GO:0002819), regulation of cellular response to heat (GO:1900034), negative regulation of catalytic activity (GO:0043086), response to cytokine (GO:0034097), regulation of insulin receptor signaling pathway (GO:0046626), positive regulation of phosphorus metabolic process (GO:0010562), positive regulation of DNA metabolic process (GO:0051054), cellular response to starvation (GO:0009267), regulation of hydrolase activity (GO:0051336), positive regulation of programmed cell death (GO:0043068), positive regulation of cellular carbohydrate metabolic process (GO:0010676), negative regulation of intracellular signal transduction (GO:1902532), regulation of carbohydrate metabolic process (GO:0006109), regulation of apoptotic signaling pathway (GO:2001233), negative regulation of oxidative stress-induced cell death (GO:1903202), positive regulation of DNA repair (GO:0045739), regulation of histone methylation (GO:0031060), negative regulation of DNA-binding transcription factor activity (GO:0043433), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), blood vessel morphogenesis (GO:0048514), nucleolar chromatin organization (GO:1990700), positive regulation of epithelial cell migration (GO:0010634), positive regulation of protein metabolic process (GO:0051247), positive regulation of adaptive immune response (GO:0002821), negative regulation of macromolecule biosynthetic process (GO:0010558), positive regulation of cellular catabolic process (GO:0031331), organelle organization (GO:0006996), regulation of cellular catabolic process (GO:0031329), negative regulation of RNA metabolic process (GO:0051253), regulation of intracellular signal transduction (GO:1902531), regulation of phosphorus metabolic process (GO:0051174), regulation of apoptotic process (GO:0042981), negative regulation of TOR signaling (GO:0032007), positive regulation of phosphate metabolic process (GO:0045937), regulation of RNA biosynthetic process (GO:2001141), regulation of gluconeogenesis (GO:0006111), DNA repair (GO:0006281), peptidyl-amino acid modification (GO:0018193), cellular response to cytokine stimulus (GO:0071345), protein deacylation (GO:0035601), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), chromatin remodeling (GO:0006338), regulation of kinase activity (GO:0043549), regulation of protein kinase B signaling (GO:0051896), positive regulation of RNA biosynthetic process (GO:1902680), cellular response to glucose starvation (GO:0042149), positive regulation of protein modification process (GO:0031401), cellular response to transforming growth factor beta stimulus (GO:0071560), positive regulation of apoptotic process (GO:0043065), regulation of intrinsic apoptotic signaling pathway (GO:2001242), positive regulation of endothelial cell proliferation (GO:0001938), positive regulation of transferase activity (GO:0051347), regulation of signal transduction by p53 class mediator (GO:1901796), regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902175), regulation of DNA repair (GO:0006282), protein modification by small protein conjugation or removal (GO:0070647), modification-dependent macromolecule catabolic process (GO:0043632), protein acylation (GO:0043543), regulation of histone H3-K9 methylation (GO:0051570), cellular response to light stimulus (GO:0071482), regulation of MHC class II biosynthetic process (GO:0045346), nucleus organization (GO:0006997), regulation of I-kappaB kinase/NF-kappaB signaling (GO:0043122), negative regulation of I-kappaB kinase/NF-kappaB signaling (GO:0043124), response to tumor necrosis factor (GO:0034612), cellular response to hydrogen peroxide (GO:0070301), negative regulation of phosphate metabolic process (GO:0045936), positive regulation of MHC class II biosynthetic process (GO:0045348), positive regulation of macroautophagy (GO:0016239), histone modification (GO:0016570), regulation of TOR signaling (GO:0032006), regulation of deoxyribonuclease activity (GO:0032070), regulation of proteolysis (GO:0030162), negative regulation of protein modification process (GO:0031400), macromolecule deacylation (GO:0098732), regulation of peptidase activity (GO:0052547), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), negative regulation of signal transduction by p53 class mediator (GO:1901797), transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0007178), regulation of blood vessel endothelial cell migration (GO:0043535), negative regulation of transferase activity (GO:0051348), response to UV (GO:0009411), regulation of endothelial cell proliferation (GO:0001936), regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043516), positive regulation of hydrolase activity (GO:0051345), negative regulation of RNA biosynthetic process (GO:1902679), regulation of androgen receptor signaling pathway (GO:0060765), cellular response to reactive oxygen species (GO:0034614), rDNA heterochromatin formation (GO:0000183), proteasomal protein catabolic process (GO:0010498), regulation of protein modification process (GO:0031399), regulation of macroautophagy (GO:0016241), negative regulation of apoptotic process (GO:0043066), positive regulation of endothelial cell migration (GO:0010595), regulation of DNA-templated transcription (GO:0006355), proteolysis involved in protein catabolic process (GO:0051603), regulation of phosphate metabolic process (GO:0019220), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), epigenetic regulation of gene expression (GO:0040029), negative regulation of protein kinase B signaling (GO:0051898), negative regulation of gene expression, epigenetic (GO:0045814), cellular response to decreased oxygen levels (GO:0036294), positive regulation of proteolysis (GO:0045862), negative regulation of NF-kappaB transcription factor activity (GO:0032088), negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902176), positive regulation of gluconeogenesis (GO:0045722), positive regulation of peptidase activity (GO:0010952), regulation of endopeptidase activity (GO:0052548), negative regulation of protein acetylation (GO:1901984), regulation of protein kinase activity (GO:0045859), positive regulation of nucleic acid-templated transcription (GO:1903508), positive regulation of phosphorylation (GO:0042327), positive regulation of protein phosphorylation (GO:0001934), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), modification-dependent protein catabolic process (GO:0019941), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), negative regulation of histone modification (GO:0031057), positive regulation of kinase activity (GO:0033674), regulation of histone modification (GO:0031056), negative regulation of kinase activity (GO:0033673), regulation of transcription by glucose (GO:0046015), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), peptidyl-lysine modification (GO:0018205), histone deacetylation (GO:0016575), regulation of protein acetylation (GO:1901983), cellular response to UV (GO:0034644), positive regulation of histone modification (GO:0031058), regulation of protein phosphorylation (GO:0001932), nucleotide-excision repair (GO:0006289), heterochromatin formation (GO:0031507), negative regulation of phosphorylation (GO:0042326), protein deacetylation (GO:0006476), negative regulation of DNA-templated transcription (GO:0045892), heterochromatin organization (GO:0070828), regulation of nucleic acid-templated transcription (GO:1903506), regulation of protein deacetylation (GO:0090311), protein modification by small protein conjugation (GO:0032446), nucleolus organization (GO:0007000), regulation of phosphorylation (GO:0042325), negative regulation of protein phosphorylation (GO:0001933), positive regulation of blood vessel endothelial cell migration (GO:0043536), positive regulation of protein deacetylation (GO:0090312), pyrimidine dimer repair (GO:0006290), UV-damage excision repair (GO:0070914), negative regulation of nucleic acid-templated transcription (GO:1903507), transforming growth factor beta receptor signaling pathway (GO:0007179), protein acetylation (GO:0006473), cellular response to tumor necrosis factor (GO:0071356), negative regulation of histone acetylation (GO:0035067), regulation of protein serine/threonine kinase activity (GO:0071900), ubiquitin-dependent protein catabolic process (GO:0006511), negative regulation of transcription by RNA polymerase II (GO:0000122), histone H3 deacetylation (GO:0070932), regulation of cysteine-type endopeptidase activity (GO:2000116), protein ubiquitination (GO:0016567), peptidyl-lysine acetylation (GO:0018394), negative regulation of protein kinase activity (GO:0006469), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of histone deacetylation (GO:0031063), facultative heterochromatin formation (GO:0140718), negative regulation of peptidyl-lysine acetylation (GO:2000757), positive regulation of endopeptidase activity (GO:0010950), regulation of peptidyl-lysine acetylation (GO:2000756), positive regulation of protein kinase activity (GO:0045860), regulation of histone acetylation (GO:0035065), positive regulation of histone deacetylation (GO:0031065), negative regulation of protein serine/threonine kinase activity (GO:0071901), regulation of cAMP-dependent protein kinase activity (GO:2000479), positive regulation of cysteine-type endopeptidase activity (GO:2001056), regulation of cysteine-type endopeptidase activity involved in apoptotic process (GO:0043281), positive regulation of protein serine/threonine kinase activity (GO:0071902), DNA methylation-dependent heterochromatin formation (GO:0006346), positive regulation of cysteine-type endopeptidase activity involved in apoptotic process (GO:0043280)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), membrane (GO:0016020), chromatin (GO:0000785), membrane-enclosed lumen (GO:0031974), cytosol (GO:0005829), envelope (GO:0031975), catalytic complex (GO:1902494), nuclear protein-containing complex (GO:0140513), cytoplasm (GO:0005737), fibrillar center (GO:0001650), endomembrane system (GO:0012505), nuclear body (GO:0016604), nucleoplasm (GO:0005654), PML body (GO:0016605), organelle membrane (GO:0031090), organelle envelope (GO:0031967), heterochromatin (GO:0000792), euchromatin (GO:0000791), transferase complex (GO:1990234), intracellular organelle (GO:0043229), methyltransferase complex (GO:0034708), non-membrane-bounded organelle (GO:0043228), mitochondrion (GO:0005739), PcG protein complex (GO:0031519), organelle lumen (GO:0043233), nuclear envelope (GO:0005635), histone methyltransferase complex (GO:0035097), chromatin silencing complex (GO:0005677), membrane-bounded organelle (GO:0043227), nuclear membrane (GO:0031965), intracellular membrane-bounded organelle (GO:0043231), intracellular non-membrane-bounded organelle (GO:0043232), rDNA heterochromatin (GO:0033553), organelle inner membrane (GO:0019866), intracellular organelle lumen (GO:0070013), ESC/E(Z) complex (GO:0035098), nucleolus (GO:0005730), nuclear inner membrane (GO:0005637), nucleus (GO:0005634), nuclear lumen (GO:0031981), chromosome (GO:0005694)

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Deep Research Bioreason Rl

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Exported on March 22, 2026 at 01:49 AM

Organism: Homo sapiens

Sequence:

MADEAALALQPGGSPSAAGADREAASSPAGEPLRKRPRRDGPGLERSPGEPGGAAPEREVPAAARGCPGAAAAALWREAEAEAAAAGGEQEAQATAAAGEGDNGPGLQGPSREPPLADNLYDEDDDDEGEEEEEAAAAAIGYRDNLLFGDEIITNGFHSCESDEEDRASHASSSDWTPRPRIGPYTFVQQHLMIGTDPRTILKDLLPETIPPPELDDMTLWQIVINILSEPPKRKKRKDINTIEDAVKLLQECKKIIVLTGAGVSVSCGIPDFRSRDGIYARLAVDFPDLPDPQAMFDIEYFRKDPRPFFKFAKEIYPGQFQPSLCHKFIALSDKEGKLLRNYTQNIDTLEQVAGIQRIIQCHGSFATASCLICKYKVDCEAVRGDIFNQVVPRCPRCPADEPLAIMKPEIVFFGENLPEQFHRAMKYDKDEVDLLIVIGSSLKVRPVALIPSSIPHEVPQILINREPLPHLHFDVELLGDCDVIINELCHRLGGEYAKLCCNPVKLSEITEKPPRTQKELAYLSELPPTPLHVSEDSSSPERTSPPDSSVIVTLLDQAAKSNDDLDVSESKGCMEEKPQEVQTSRNVESIAEQMENPDLKNVGSSTGEKNERTSVAGTVRKCWPNRVAKEQISRRLDGNQYLFLPPNRYIFHGAEVYSDSEDDVLSSSSCGSNSDSGTCQSPSLEEPMEDESEIEEFYNGLEDEPDVPERAGGAGFGTDGDDQEAINEAISVKQEVTDMNYPSNKS

Thinking Trace

Functional Summary

UniProt Summary

NAD-dependent protein deacylase. Acts as a lysine deacetylase, catalyzing the NAD-dependent hydrolysis of acetylated lysine residues (By similarity).

InterPro Domains

DHS-like NAD/FAD-binding domain superfamily (IPR029035, homologous_superfamily) — residues 229-508
NAD-dependent sirtuin protein deacylases (IPR050134, family) — residues 235-506
Sirtuin family, catalytic core domain (IPR026590, domain) — residues 236-496
Sirtuin family (IPR003000, family) — residues 261-447
Sirtuin, catalytic core small domain superfamily (IPR026591, homologous_superfamily) — residues 267-419

GO Terms

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Deep Research Falcon

(SIRT1-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
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start_time: '2026-01-18T20:46:54.631769'
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template_file: templates/gene_research_go_focused.md
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organism: human
gene_id: SIRT1
gene_symbol: SIRT1
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protein_description: 'RecName: Full=NAD-dependent protein deacetylase sirtuin-1
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ECO:0000269|PubMed:32034146}; AltName: Full=NAD-dependent protein deacylase sirtuin-1
{ECO:0000305}; EC=2.3.1.- {ECO:0000269|PubMed:28497810}; AltName: Full=Regulatory
protein SIR2 homolog 1; AltName: Full=SIR2-like protein 1; Short=hSIR2; Contains:
RecName: Full=SirtT1 75 kDa fragment {ECO:0000303|PubMed:21987377}; Short=75SirT1
{ECO:0000303|PubMed:21987377};'
gene_info: Name=SIRT1 {ECO:0000303|PubMed:12535671, ECO:0000312|HGNC:HGNC:14929};
Synonyms=SIR2L1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the sirtuin family. Class I subfamily.
protein_domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases.
(IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Ssirtuin_cat_dom.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q96EB6
Protein Description: RecName: Full=NAD-dependent protein deacetylase sirtuin-1 {ECO:0000305}; Short=hSIRT1; EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236, ECO:0000269|PubMed:12006491, ECO:0000269|PubMed:22918831, ECO:0000269|PubMed:30409912, ECO:0000269|PubMed:32034146}; AltName: Full=NAD-dependent protein deacylase sirtuin-1 {ECO:0000305}; EC=2.3.1.- {ECO:0000269|PubMed:28497810}; AltName: Full=Regulatory protein SIR2 homolog 1; AltName: Full=SIR2-like protein 1; Short=hSIR2; Contains: RecName: Full=SirtT1 75 kDa fragment {ECO:0000303|PubMed:21987377}; Short=75SirT1 {ECO:0000303|PubMed:21987377};
Gene Information: Name=SIRT1 {ECO:0000303|PubMed:12535671, ECO:0000312|HGNC:HGNC:14929}; Synonyms=SIR2L1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the sirtuin family. Class I subfamily.
Key Domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases. (IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Ssirtuin_cat_dom. (IPR026590)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SIRT1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SIRT1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene SIRT1 (gene ID: SIRT1, UniProt: Q96EB6) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q96EB6
Protein Description: RecName: Full=NAD-dependent protein deacetylase sirtuin-1 {ECO:0000305}; Short=hSIRT1; EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236, ECO:0000269|PubMed:12006491, ECO:0000269|PubMed:22918831, ECO:0000269|PubMed:30409912, ECO:0000269|PubMed:32034146}; AltName: Full=NAD-dependent protein deacylase sirtuin-1 {ECO:0000305}; EC=2.3.1.- {ECO:0000269|PubMed:28497810}; AltName: Full=Regulatory protein SIR2 homolog 1; AltName: Full=SIR2-like protein 1; Short=hSIR2; Contains: RecName: Full=SirtT1 75 kDa fragment {ECO:0000303|PubMed:21987377}; Short=75SirT1 {ECO:0000303|PubMed:21987377};
Gene Information: Name=SIRT1 {ECO:0000303|PubMed:12535671, ECO:0000312|HGNC:HGNC:14929}; Synonyms=SIR2L1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the sirtuin family. Class I subfamily.
Key Domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases. (IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Ssirtuin_cat_dom. (IPR026590)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SIRT1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene SIRT1 (gene ID: SIRT1, UniProt: Q96EB6) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan overview and verification
We verified the target as human SIRT1 (gene SIRT1; UniProt Q96EB6), a Class I sirtuin with a conserved Rossmann-like NAD-binding catalytic core and zinc-finger motif. The gene symbol, organism (Homo sapiens), and domain family match UniProt and recent reviews (including an endothelial-focused 2024 update) (campagna2024themultifacetedrole pages 1-2, campagna2024themultifacetedrole pages 2-3).

Key concepts and definitions with current understanding
- Identity and enzyme class: SIRT1 is an NAD+-dependent lysine deacetylase/deacylase. It couples lysine acyl removal to NAD+ cleavage, producing nicotinamide and 2′-O-acetyl-ADP-ribose (EC 2.3.1.286). Sirtuins share a conserved catalytic mechanism centered on an NAD-binding Rossmann-like fold and a catalytic histidine that facilitates the reaction chemistry (Castiello 2025 review) (castiello2025newfrontiersfor pages 67-70). SIRT1 deacetylates both histone and non‑histone substrates and is a key metabolic and stress-response regulator (Campagna et al., Cells, 2024; Bursch et al., Molecules, 2024) (campagna2024themultifacetedrole pages 1-2, bursch2024currenttrendsin pages 6-7). URLs: https://doi.org/10.3390/cells13171469 (Sep 2024); https://doi.org/10.3390/molecules29051185 (Mar 2024).
- Substrate scope: Histones include H4K16 (preferentially) and H3K9/H3K14/H4K8/H4K12. Non‑histone substrates include p53 (notably K382), NF‑κB p65/RelA, FOXO factors, HIF1α/HIF2α, and PGC‑1α. These deacetylation events modulate apoptosis, chromatin state, inflammation, hypoxia responses, and mitochondrial biogenesis (Campagna 2024; Castiello 2025) (campagna2024themultifacetedrole pages 1-2, castiello2025newfrontiersfor pages 67-70, castiello2025newfrontiersfor pages 77-79).

Recent developments and latest research (prioritize 2023–2024)
- Mechanism and allosteric activation: Contemporary analyses emphasize that small‑molecule SIRT1-activating compounds (STACs) function allosterically by lowering the Km for certain peptide substrates in a substrate‑sequence‑dependent manner, with a defined STAC-binding region and sensitivity to mutations such as E230K. This preserves NAD+ dependence and supports the canonical deacetylation chemistry (Bursch et al., 2024, Molecules; review of mechanism and kinetic behavior) (bursch2024currenttrendsin pages 6-7). URL: https://doi.org/10.3390/molecules29051185 (Mar 2024).
- Post‑translational regulation and localization: A 2024 endothelial review summarizes emerging details on SIRT1 regulation by phosphorylation (e.g., CDK5, HIPK2, JAK1), SUMOylation (Lys734), ubiquitination (e.g., SMURF2), S‑nitrosylation (Cys387/Cys390), O‑GlcNAcylation (Ser549), and other redox modifications, which together tune localization, stability, and activity. This work also highlights the connection between NAD+ biosynthesis pathways and endothelial aging (Campagna et al., Cells, 2024) (campagna2024themultifacetedrole pages 2-3, campagna2024themultifacetedrole pages 1-2). URL: https://doi.org/10.3390/cells13171469 (Sep 2024).

Primary function, reaction, and substrate specificity
- Catalyzed reaction: SIRT1 is a lysine deacetylase/deacylase that uses NAD+ to remove acetyl (and certain acyl) groups from ε‑lysines, yielding deacetylated protein, nicotinamide, and 2′‑O‑acetyl‑ADP‑ribose (Castiello 2025) (castiello2025newfrontiersfor pages 67-70).
- Substrate specificity and kinetics: SIRT1 targets specific histone lysines (e.g., H4K16ac) and many non‑histone proteins. STACs exhibit substrate‑sequence dependence, activating deacetylation preferentially on peptides with certain C‑terminal aromatic/hydrophobic residues; this is consistent with direct activation of SIRT1 rather than altered NAD+ affinity (Bursch 2024) (bursch2024currenttrendsin pages 6-7).
- Exemplar substrates: p53 K382 deacetylation attenuates p53 transcriptional activity and influences apoptosis; SIRT1 deacetylates FOXO family members to adjust stress responses; deacetylation of NF‑κB p65 dampens inflammatory transcription; SIRT1 deacetylation of HIF1α/HIF2α modulates hypoxia signaling; and deacetylation of PGC‑1α promotes mitochondrial biogenesis and oxidative metabolism (Campagna 2024; Castiello 2025) (campagna2024themultifacetedrole pages 1-2, castiello2025newfrontiersfor pages 67-70, castiello2025newfrontiersfor pages 77-79).

Subcellular localization and regulation
- Localization: SIRT1 is predominantly nuclear but undergoes regulated nucleo‑cytoplasmic shuttling; it contains an N‑terminal nuclear localization signal and can exhibit nuclear vs cytoplasmic distribution depending on cell type and context (Campagna 2024; Castiello 2025) (campagna2024themultifacetedrole pages 1-2, castiello2025newfrontiersfor pages 60-63). Nuclear enrichment is typical in endothelium and cardiomyocytes, with context‑dependent cytoplasmic pools described. Localization and activity are controlled by PTMs and cellular NAD+ availability (Campagna 2024) (campagna2024themultifacetedrole pages 2-3, campagna2024themultifacetedrole pages 1-2).

Mechanistic pathway roles and precise nodes
- DNA damage and chromatin regulation: SIRT1 deacetylates p53 and Ku70, modulating apoptosis and DNA repair, and promotes heterochromatin formation via histone deacetylation (e.g., H4K16ac) (Castiello 2025; Campagna 2024) (castiello2025newfrontiersfor pages 67-70, campagna2024themultifacetedrole pages 1-2).
- Metabolism and mitochondrial biogenesis: SIRT1 deacetylates PGC‑1α, advancing oxidative metabolism and mitochondrial biogenesis (Campagna 2024; Castiello 2025) (campagna2024themultifacetedrole pages 1-2, castiello2025newfrontiersfor pages 67-70).
- Inflammation: SIRT1 deacetylates NF‑κB p65/RelA, thereby repressing pro‑inflammatory transcription. Through this node, SIRT1 is positioned as an anti‑inflammatory regulator in multiple tissues (Castiello 2025; Campagna 2024) (castiello2025newfrontiersfor pages 77-79, campagna2024themultifacetedrole pages 1-2).
- Hypoxia signaling: Deacetylation of HIF1α/HIF2α modulates hypoxia responses in endothelial and other contexts (Castiello 2025) (castiello2025newfrontiersfor pages 77-79).
- Cardiovascular context: Reviews highlight SIRT1 roles in endothelial function, oxidative stress control, senescence, and atherosclerosis progression. In the cardiovascular system, SIRT1’s dynamic localization and regulation are emphasized as central to its protective actions (Dinislam 2026; Campagna 2024) (dinislam2026sirt1thefirst pages 1-3, campagna2024themultifacetedrole pages 1-2). URL: https://doi.org/10.3389/fphar.2025.1668718 (Jan 2026); https://doi.org/10.3390/cells13171469 (Sep 2024).

Pharmacologic modulators, selectivity, and clinical/translational notes (2023–2024 emphasis)
- Natural and synthetic activators: Resveratrol is the prototype natural STAC, though direct activation mechanisms have been debated; synthetic STACs (SRT1720, SRT2104, SRT1460, SRT2183) show potent SIRT1‑dependent activity in vitro and in cells, often lowering Km for specific peptide substrates; substrate sequence near the acetyl‑lysine is critical, and E230K mutation attenuates STAC activation without affecting basal kinetics (Bursch 2024) (bursch2024currenttrendsin pages 6-7). URL: https://doi.org/10.3390/molecules29051185 (Mar 2024).
- NAD+ boosters: Modulating NAD+ via precursors (e.g., NR, NAM) can influence SIRT1 activity, with translational interest in metabolic and vascular applications (Campagna 2024; Bursch 2024) (campagna2024themultifacetedrole pages 1-2, bursch2024currenttrendsin pages 6-7).
- Clinical observations: SRT2104 advanced to human testing with general tolerability but poor oral bioavailability reported; in short studies, lipid profile improvements were observed (lower cholesterol and triglycerides; increased HDL/LDL ratio) (Bursch 2024) (bursch2024currenttrendsin pages 6-7). Resveratrol has been tested clinically with mixed efficacy, reflecting bioavailability and target‑engagement challenges (Bursch 2024) (bursch2024currenttrendsin pages 6-7).

Current applications and implementations
- Vascular aging and endothelium: Mechanistic and translational efforts are focused on boosting SIRT1 activity to counter endothelial senescence and vascular dysfunction, integrating NAD+ metabolism and PTM control of SIRT1 (Campagna 2024) (campagna2024themultifacetedrole pages 1-2, campagna2024themultifacetedrole pages 2-3).
- Broader cardiometabolic context: Reviews underscore SIRT1 involvement across endothelial function, oxidative stress, inflammation, and senescence in cardiovascular disease, supporting continued development of SIRT1 modulators (Dinislam 2026) (dinislam2026sirt1thefirst pages 1-3).

Expert opinions and analysis from authoritative sources
- Endothelial SIRT1: The 2024 Cells review synthesizes mechanistic regulation (PTMs, NAD+ pathways), histone and non‑histone substrate actions, and therapeutic angles for vascular aging, emphasizing the need for precise modulation of SIRT1 activity and localization (Campagna et al., 2024) (campagna2024themultifacetedrole pages 1-2, campagna2024themultifacetedrole pages 2-3).
- Sirtuin modulation landscape: The 2024 Molecules review highlights lessons from STACs—substrate‑sequence dependence, defined binding determinants, the E230K sensitivity, and translational bottlenecks (bioavailability/off‑targets)—guiding next‑generation SIRT1 modulators (Bursch et al., 2024) (bursch2024currenttrendsin pages 6-7).

Relevant statistics and data from recent studies
- STAC selectivity and kinetics: STACs were reported to confer large fold‑increases in apparent SIRT1 activity on compatible peptide substrates (and selectivity over SIRT2/3) in biochemical assays; these effects associate with reduced Km for acetyl‑lysine without altering the Km for NAD+ (Bursch 2024) (bursch2024currenttrendsin pages 6-7).
- Translational lipid effects: In short clinical investigations summarized in 2024, SRT2104 lowered total cholesterol and triglycerides and raised the HDL/LDL ratio but suffered from poor oral bioavailability, underscoring the medicinal chemistry gap to clinical efficacy (Bursch 2024) (bursch2024currenttrendsin pages 6-7).

Concise functional summary table
| Category | Key facts | Primary recent sources |
|---|---|---|
| Identity & domains | - Human SIRT1 (UniProt Q96EB6), ~747 aa
- Class I sirtuin; NAD+-dependent deacetylase with Rossmann-like NAD-binding fold and zinc-finger motif | Campagna et al., Cells 2024 — https://doi.org/10.3390/cells13171469 (campagna2024themultifacetedrole pages 1-2) |
| Enzymatic reaction & mechanism | - NAD+-dependent deacetylation (EC 2.3.1.286): yields nicotinamide + 2'-O-acetyl-ADP-ribose
- Conserved mechanism: NAD+ binding (Rossmann fold), catalytic His-mediated chemistry
- Allosteric STACs lower Km for acyl-lysine substrates (substrate-sequence dependence) | Castiello 2025 — URL not provided (castiello2025newfrontiersfor pages 67-70); Bursch et al., Molecules 2024 — https://doi.org/10.3390/molecules29051185 (bursch2024currenttrendsin pages 6-7) |
| Exemplary substrates (histone & non-histone) | - Histone: preferentially deacetylates H4K16ac (also H3K9/K14)
- Non-histone: p53 (K382) deacetylation; FOXO1/3; NF-κB RelA/p65; HIF1α/2α; PGC-1α (mitochondrial regulator) | Campagna et al., Cells 2024 — https://doi.org/10.3390/cells13171469 (campagna2024themultifacetedrole pages 1-2); Castiello 2025 — URL not provided (castiello2025newfrontiersfor pages 67-70) |
| Subcellular localization & regulation | - Predominantly nuclear with regulated nucleo–cytoplasmic shuttling; NLS around aa41–46 reported
- Localization/activity modulated by PTMs (phosphorylation, SUMOylation, ubiquitination, S‑nitrosylation, O‑GlcNAcylation) and NAD+ availability
- Interacting partners and stress context alter localization/stability | Campagna et al., Cells 2024 — https://doi.org/10.3390/cells13171469 (campagna2024themultifacetedrole pages 2-3, campagna2024themultifacetedrole pages 1-2) |
| Pathway nodes (mechanistic roles) | - DNA damage response: deacetylates p53, Ku70 → modulates apoptosis/repair
- Chromatin regulation: H4K16 deacetylation → heterochromatin/transcriptional repression
- Metabolism: deacetylates PGC‑1α → promotes mitochondrial biogenesis/oxidative metabolism
- Circadian: deacetylates core clock components (BMAL1/PER2) to tune rhythms
- Inflammation: deacetylates NF‑κB RelA/p65 and suppresses NLRP3-driven inflammation | Castiello 2025 — URL not provided (castiello2025newfrontiersfor pages 67-70, castiello2025newfrontiersfor pages 77-79); Campagna et al., Cells 2024 — https://doi.org/10.3390/cells13171469 (campagna2024themultifacetedrole pages 1-2) |
| Pharmacologic modulators | - Resveratrol: natural STAC; direct SIRT1 activation contested in mechanism studies
- Synthetic STACs (SRT1720, SRT2104): allosteric activation, substrate-sequence dependence; E230K mutation reduces STAC activation in mechanistic studies
- NAD+ boosters (nicotinamide riboside, NAM): increase NAD+ to support SIRT1 activity | Bursch et al., Molecules 2024 — https://doi.org/10.3390/molecules29051185 (bursch2024currenttrendsin pages 6-7); Dinislam et al., Frontiers in Pharmacology 2026 — https://doi.org/10.3389/fphar.2025.1668718 (dinislam2026sirt1thefirst pages 1-3) |
| Clinical / translational notes | - SRT2104 progressed to human testing: generally tolerated but reported poor oral bioavailability; small lipid-profile benefits observed in short studies
- Resveratrol tested in multiple trials with mixed outcomes; translational efficacy variable
- NAD+ precursor trials ongoing with context-dependent results | Bursch et al., Molecules 2024 — https://doi.org/10.3390/molecules29051185 (bursch2024currenttrendsin pages 6-7); Dinislam et al., Frontiers in Pharmacology 2026 — https://doi.org/10.3389/fphar.2025.1668718 (dinislam2026sirt1thefirst pages 1-3) |
| Expert reviews | - Vascular aging: Campagna et al., Cells 2024 — comprehensive endothelial SIRT1 review
- Sirtuin modulators: Bursch et al., Molecules 2024 — review of activator/inhibitor development
- Broad epigenetics & pathway context: Castiello 2025 — general review | Campagna et al., Cells 2024 — https://doi.org/10.3390/cells13171469 (campagna2024themultifacetedrole pages 1-2); Bursch et al., Molecules 2024 — https://doi.org/10.3390/molecules29051185 (bursch2024currenttrendsin pages 6-7); Castiello 2025 — URL not provided (castiello2025newfrontiersfor pages 60-63) |

Table: Compact functional summary table for human SIRT1 (UniProt Q96EB6) showing core identity, mechanism, substrates, localization/regulation, pathway roles, modulators, clinical notes and key recent sources (2023–2024). Useful as a quick reference for mechanistic annotation and literature starting points.

Conclusion
Human SIRT1 (Q96EB6) is a nuclear‑biased, NAD+-dependent deacetylase that orchestrates genome regulation, stress responses, and metabolism through precise deacetylation of histones (e.g., H4K16) and non‑histone factors (p53, NF‑κB p65, FOXOs, HIFs, PGC‑1α). Recent work refines the allosteric activation model of SIRT1 by STACs, revealing stringent substrate‑sequence requirements and explaining variable outcomes across assays and trials. 2023–2024 reviews emphasize PTM‑dependent control of SIRT1 activity and localization, integration with NAD+ biosynthesis, and translational opportunities in vascular aging and cardiometabolism. Future clinical success likely hinges on improving bioavailability and target engagement while leveraging context‑specific substrate preference and subcellular localization to achieve pathway‑precise modulation (Campagna 2024; Bursch 2024; Castiello 2025; Dinislam 2026) (campagna2024themultifacetedrole pages 1-2, campagna2024themultifacetedrole pages 2-3, bursch2024currenttrendsin pages 6-7, castiello2025newfrontiersfor pages 67-70, castiello2025newfrontiersfor pages 77-79, dinislam2026sirt1thefirst pages 1-3).

References

(campagna2024themultifacetedrole pages 1-2): Roberto Campagna, Laura Mazzanti, Veronica Pompei, Sonila Alia, Arianna Vignini, and Monica Emanuelli. The multifaceted role of endothelial sirt1 in vascular aging: an update. Cells, 13:1469, Sep 2024. URL: https://doi.org/10.3390/cells13171469, doi:10.3390/cells13171469. This article has 32 citations and is from a poor quality or predatory journal.
(campagna2024themultifacetedrole pages 2-3): Roberto Campagna, Laura Mazzanti, Veronica Pompei, Sonila Alia, Arianna Vignini, and Monica Emanuelli. The multifaceted role of endothelial sirt1 in vascular aging: an update. Cells, 13:1469, Sep 2024. URL: https://doi.org/10.3390/cells13171469, doi:10.3390/cells13171469. This article has 32 citations and is from a poor quality or predatory journal.
(castiello2025newfrontiersfor pages 67-70): C Castiello. New frontiers for epigenetics: from immunology to cardiovascular diseases and beyond. Unknown journal, 2025.
(bursch2024currenttrendsin pages 6-7): Karina L. Bursch, Christopher J. Goetz, and Brian C. Smith. Current trends in sirtuin activator and inhibitor development. Molecules, 29:1185, Mar 2024. URL: https://doi.org/10.3390/molecules29051185, doi:10.3390/molecules29051185. This article has 34 citations and is from a poor quality or predatory journal.
(castiello2025newfrontiersfor pages 77-79): C Castiello. New frontiers for epigenetics: from immunology to cardiovascular diseases and beyond. Unknown journal, 2025.
(castiello2025newfrontiersfor pages 60-63): C Castiello. New frontiers for epigenetics: from immunology to cardiovascular diseases and beyond. Unknown journal, 2025.
(dinislam2026sirt1thefirst pages 1-3): Khuzin Dinislam, Muneer Ahmed Khoso, Valeriy A. Kataev, Svetlana Meshcheryakova, Heng Liu, Ling Liu, Madi Guo, Song Wang, Han Lou, Yong Zhang, and Xin Liu. Sirt1: the first key to unlocking the mystery of cardiovascular diseases. Frontiers in Pharmacology, Jan 2026. URL: https://doi.org/10.3389/fphar.2025.1668718, doi:10.3389/fphar.2025.1668718. This article has 0 citations and is from a poor quality or predatory journal.

Citations

castiello2025newfrontiersfor pages 67-70
bursch2024currenttrendsin pages 6-7
castiello2025newfrontiersfor pages 77-79
campagna2024themultifacetedrole pages 1-2
castiello2025newfrontiersfor pages 60-63
campagna2024themultifacetedrole pages 2-3
https://doi.org/10.3390/cells13171469
https://doi.org/10.3390/molecules29051185
https://doi.org/10.3389/fphar.2025.1668718
https://doi.org/10.3390/cells13171469,
https://doi.org/10.3390/molecules29051185,
https://doi.org/10.3389/fphar.2025.1668718,

Bioreason Rl Review

(SIRT1-bioreason-rl-review.md)

BioReason-Pro RL Review: SIRT1 (human)

Source: SIRT1-deep-research-bioreason-rl.md

Correctness: 4/5
Completeness: 3/5

Functional Summary Review

The BioReason functional summary states:

A soluble human NAD-dependent lysine deacylase that uses a sirtuin catalytic core to reverse acylation marks on proteins and histones, thereby tuning chromatin state, transcriptional programs, and cell-fate pathways. Its soluble fold and regulatory role indicate distribution between cytoplasm and nucleus, where it binds nicotinamide adenine cofactors to drive deacylation chemistry and modulate apoptotic and stress-responsive networks through dynamic control of lysine acylation.

This is a largely accurate summary. The curated review describes SIRT1 as an "NAD-dependent protein deacetylase that catalyzes removal of acetyl groups from lysine residues of histones (preferentially H4K16, H3K9, H3K14) and numerous non-histone proteins including p53, NF-kB RelA/p65, FOXO factors, HIF1alpha/HIF2alpha, and PGC-1alpha." BioReason correctly captures the NAD-dependent deacylase activity, histone and protein substrates, chromatin regulation, and nucleocytoplasmic distribution.

The use of "deacylase" rather than the more specific "deacetylase" is technically correct (sirtuins can remove other acyl groups) but slightly imprecise for SIRT1, whose primary activity is deacetylation.

Notable gaps:
1. No specific substrates are named (p53, FOXO, NF-kB are key SIRT1 targets)
2. The role in circadian rhythm regulation is not mentioned (curated review includes this)
3. Metabolic regulation (gluconeogenesis, insulin sensitivity, fatty acid oxidation) is absent
4. The aging/longevity connection is not mentioned
5. Specific histone targets (H4K16, H3K9) are not identified

The thinking trace oddly states "the molecular function resolves to... GO:0005515" (protein binding), which is not the primary molecular function -- NAD-dependent protein deacetylase activity (GO:0034979) is.

Comparison with interpro2go:

The interpro2go annotations from IPR003000 (Sirtuin family) and IPR026590 (Sirtuin catalytic core) would map to NAD-dependent protein deacetylase activity and histone deacetylase activity. BioReason correctly derives these from the domain architecture. The narrative about chromatin regulation and stress-responsive networks adds modest context beyond interpro2go but misses the specific biological programs (metabolism, circadian rhythm) that define SIRT1's unique role among sirtuins.

Notes on thinking trace

The trace systematically identifies the DHS-like NAD/FAD-binding domain and nested sirtuin signatures. The mechanistic description of NAD-coupled lysine deacylation chemistry is accurate. However, the assignment of GO:0005515 as the molecular function label is puzzling and appears to be an error in the reasoning chain.

📄 View Raw YAML

id: Q96EB6
gene_symbol: SIRT1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NAD-dependent protein deacetylase that catalyzes removal of acetyl 
  groups from lysine residues of histones (preferentially H4K16, H3K9, H3K14) 
  and numerous non-histone proteins including p53, NF-kB RelA/p65, FOXO factors,
  HIF1alpha/HIF2alpha, and PGC-1alpha. The core enzymatic function couples NAD+ 
  cleavage to lysine deacetylation, producing nicotinamide and 
  2-O-acetyl-ADP-ribose. Functions in transcriptional regulation through 
  heterochromatin formation and as a transcription corepressor. Has broad 
  pleiotropic effects on metabolism, stress responses, DNA damage response, and 
  aging through deacetylation of diverse substrates.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 is predominantly nuclear with regulated nucleo-cytoplasmic 
        shuttling. Contains an N-terminal nuclear localization signal. Nuclear 
        enrichment is well-established through multiple IDA studies 
        (PMID:11672523, PMID:20167603, PMID:20955178).
      action: ACCEPT
      reason: Core localization supported by phylogenetic inference and 
        extensive experimental evidence. SIRT1 functions primarily in the 
        nucleus for chromatin regulation and transcription factor deacetylation.
      supported_by:
        - reference_id: PMID:12006491
          supporting_text: "SIRT1, the human Sir2 homolog, is recruited to the promyelocytic
            leukemia protein (PML) nuclear bodies of mammalian cells"
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
        - reference_id: file:human/SIRT1/SIRT1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 functions as a transcriptional corepressor through histone 
        deacetylation and deacetylation of transcription factors. Experimentally
        demonstrated through IDA evidence (PMID:12535671, PMID:20955178).
      action: ACCEPT
      reason: Core molecular function well-supported by phylogenetic inference 
        and experimental evidence. SIRT1 mediates transcriptional repression 
        through heterochromatin formation and deacetylation of transcription 
        factors.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "We propose a model for SirT1-mediated heterochromatin
            formation that includes deacetylation of histone tails, recruitment and
            deacetylation of histone H1, and spreading of hypomethylated H3-K79 with
            resultant silencing."
  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 participates in DNA damage response through deacetylation 
        of p53, Ku70, NBS1, and other DNA repair proteins. Well-supported by 
        multiple experimental studies (PMID:18203716, PMID:19934257, 
        PMID:20100829).
      action: ACCEPT
      reason: Core biological process supported by phylogenetic inference and 
        extensive experimental evidence. SIRT1 modulates DNA damage response 
        through deacetylation of key repair proteins.
      supported_by:
        - reference_id: PMID:12006491
          supporting_text: "SIRT1 binds and deacetylates p53, a component of PML nuclear
            bodies, and it can repress p53-mediated transactivation."
  - term:
      id: GO:0031509
      label: subtelomeric heterochromatin formation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 promotes heterochromatin formation through histone 
        deacetylation. Phylogenetically conserved from yeast Sir2p which is 
        required for telomeric silencing.
      action: ACCEPT
      reason: Core biological process supported by phylogenetic inference. SIRT1
        promotes facultative heterochromatin formation through deacetylation of 
        H4K16 and H3K9.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "We propose a model for SirT1-mediated heterochromatin
            formation that includes deacetylation of histone tails, recruitment and
            deacetylation of histone H1, and spreading of hypomethylated H3-K79 with
            resultant silencing."
  - term:
      id: GO:0032041
      label: histone H3K14 deacetylase activity, NAD-dependent
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 has NAD-dependent histone H3K14 deacetylase activity. 
        Demonstrated experimentally (PMID:15469825).
      action: ACCEPT
      reason: Core molecular function. SIRT1 deacetylates H3K14 among other 
        histone lysines in an NAD-dependent manner. This is the primary 
        enzymatic activity of SIRT1.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
  - term:
      id: GO:0046969
      label: histone H3K9 deacetylase activity, NAD-dependent
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 has NAD-dependent histone H3K9 deacetylase activity. 
        Directly demonstrated experimentally (PMID:15469825).
      action: ACCEPT
      reason: Core molecular function. H3K9 deacetylation is a major activity of
        SIRT1 linked to heterochromatin formation.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
  - term:
      id: GO:0046970
      label: histone H4K16 deacetylase activity, NAD-dependent
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 has NAD-dependent histone H4K16 deacetylase activity as its
        preferential histone substrate. Directly demonstrated experimentally 
        (PMID:15469825).
      action: ACCEPT
      reason: Core molecular function. H4K16 is the preferred histone substrate 
        of SIRT1 and its deacetylation is critical for heterochromatin 
        formation.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 negatively regulates transcription through histone 
        deacetylation and heterochromatin formation.
      action: KEEP_AS_NON_CORE
      reason: Transcriptional repression is a downstream effect of chromatin
        modification rather than a singular core function.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "Gal4-SirT1 expression resulted in the deacetylation of
            H4-K16 and H3-K9, recruitment of H1 within the promoter vicinity, drastically
            reduced reporter expression"
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 localizes to the nucleoplasm. Supported by multiple IDA 
        studies and subcellular fractionation.
      action: ACCEPT
      reason: Core localization supported by phylogenetic inference and 
        experimental evidence.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "We characterized human SirT1, one of the human homologs
            of the budding yeast Sir2p, an NAD+-dependent histone deacetylase involved
            in establishing repressive chromatin"
  - term:
      id: GO:0005637
      label: nuclear inner membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 has been reported at the nuclear envelope/inner membrane 
        (PMID:15469825). May reflect association with heterochromatin at the 
        nuclear periphery.
      action: ACCEPT
      reason: Localization supported by phylogenetic inference and experimental 
        evidence. Association with nuclear envelope is consistent with 
        heterochromatin regulation at nuclear periphery.
  - term:
      id: GO:0033553
      label: rDNA heterochromatin
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIRT1 localizes to rDNA heterochromatin as part of the eNoSC 
        complex that regulates rRNA transcription in response to energy status 
        (PMID:18485871).
      action: ACCEPT
      reason: Core localization supported by phylogenetic inference and 
        experimental evidence. SIRT1 is a key component of the eNoSC complex at 
        rDNA loci.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: "eNoSC contains Nucleomethylin, which binds histone H3
            dimethylated Lys9 in the rDNA locus, in a complex with SIRT1 and SUV39H1."
  - term:
      id: GO:0000781
      label: chromosome, telomeric region
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: SIRT1 localizes to telomeric regions, consistent with its role in
        subtelomeric heterochromatin formation inherited from yeast Sir2.
      action: ACCEPT
      reason: Localization consistent with phylogenetically conserved function 
        in telomeric silencing.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Nuclear localization of SIRT1 is well-established through 
        multiple experimental studies.
      action: ACCEPT
      reason: Core localization. Duplicate of IBA annotation; IEA provides 
        broader automated coverage.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: SIRT1 modulates apoptosis through deacetylation of p53 and other 
        pro-apoptotic factors. This is a downstream consequence of its 
        deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: SIRT1 affects apoptosis through its primary deacetylase function 
        on substrates like p53 and FOXO, but apoptosis regulation is not the 
        core function of the enzyme. This is a pleiotropic effect.
  - term:
      id: GO:0007517
      label: muscle organ development
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: SIRT1 has been implicated in muscle differentiation through 
        deacetylation of MyoD and other myogenic factors.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect of SIRT1 deacetylase activity. Not 
        the core function.
  - term:
      id: GO:0016605
      label: PML body
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: SIRT1 is recruited to PML nuclear bodies upon PML overexpression 
        where it co-localizes with p53 (PMID:12006491).
      action: ACCEPT
      reason: Well-established localization. PML body recruitment is relevant to
        SIRT1 function in p53 deacetylation.
      supported_by:
        - reference_id: PMID:12006491
          supporting_text: "SIRT1, the human Sir2 homolog, is recruited to the promyelocytic
            leukemia protein (PML) nuclear bodies of mammalian cells"
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: SIRT1 is classified as a transferase (EC 2.3.1.286) because the 
        deacetylation reaction transfers the acetyl group to ADP-ribose.
      action: MODIFY
      reason: This is too general. SIRT1 has NAD-dependent protein deacetylase 
        activity which is more specific.
      proposed_replacement_terms:
        - id: GO:0034979
          label: NAD-dependent protein lysine deacetylase activity
  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: SIRT1 affects various differentiation processes through 
        deacetylation of transcription factors.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect. SIRT1 impacts differentiation in 
        multiple cell types but this is not its core function.
  - term:
      id: GO:0032436
      label: positive regulation of proteasomal ubiquitin-dependent protein 
        catabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIRT1 deacetylation can promote proteasomal degradation of some 
        substrates, including through effects on ubiquitination.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of SIRT1 deacetylase activity on protein 
        stability. Not the core function.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: NAD-dependent protein lysine deacetylase activity is the core 
        enzymatic function of SIRT1.
      action: ACCEPT
      reason: Core molecular function. This is the primary enzymatic activity of
        SIRT1.
  - term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIRT1 deacetylation can affect protein stability and degradation 
        of some substrates.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of SIRT1 deacetylase activity. Not the core 
        function.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: SIRT1 contains a zinc-finger motif in its catalytic domain that 
        coordinates zinc ions for structural stability.
      action: ACCEPT
      reason: SIRT1 contains a conserved zinc-binding domain that is essential 
        for its structure and function.
  - term:
      id: GO:0046890
      label: regulation of lipid biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIRT1 regulates lipid metabolism through deacetylation of SREBP 
        and other metabolic transcription factors.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect of SIRT1 deacetylase activity. Part of
        SIRT1 pleiotropic metabolic functions.
  - term:
      id: GO:0046970
      label: histone H4K16 deacetylase activity, NAD-dependent
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIRT1 preferentially deacetylates H4K16 among histone substrates 
        (PMID:15469825).
      action: ACCEPT
      reason: Core molecular function. H4K16 is the preferred histone substrate 
        of SIRT1.
  - term:
      id: GO:0048511
      label: rhythmic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: SIRT1 can deacetylate circadian clock components BMAL1 and PER2 
        (PMID:18662546), but this is one of many substrates. SIRT1 core function
        is NAD-dependent deacetylation with broad substrate specificity 
        including p53, NF-kB, FOXO, HIF, PGC-1alpha, and histones. Clock 
        component deacetylation is a downstream effect of the enzymatic 
        activity, not an evolved rhythmic function.
      action: MARK_AS_OVER_ANNOTATED
      reason: SIRT1 has broad substrate specificity as an NAD-dependent 
        deacetylase. While it can deacetylate clock proteins, this is one of 
        many substrates. The core function is the NAD-dependent deacetylase 
        activity, not rhythm generation. This represents an over-annotation 
        based on one particular substrate class.
  - term:
      id: GO:0050793
      label: regulation of developmental process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIRT1 affects various developmental processes through 
        deacetylation of developmental transcription factors.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect. SIRT1 has broad effects on gene 
        regulation but developmental regulation is not its core function.
  - term:
      id: GO:0051239
      label: regulation of multicellular organismal process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIRT1 affects various organismal processes through its broad 
        deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect. This is too broad and vague to be 
        informative about SIRT1 core function.
  - term:
      id: GO:0062013
      label: positive regulation of small molecule metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIRT1 regulates metabolism through deacetylation of PGC-1alpha 
        and other metabolic regulators.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. SIRT1 affects metabolism broadly but 
        this is not its core function.
  - term:
      id: GO:0070403
      label: NAD+ binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: SIRT1 binds NAD+ as an essential cofactor for its deacetylase 
        reaction. The NAD-binding Rossmann-like fold is conserved in all 
        sirtuins.
      action: ACCEPT
      reason: Core molecular function. NAD+ binding is essential for SIRT1 
        catalytic activity.
  - term:
      id: GO:0071456
      label: cellular response to hypoxia
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIRT1 deacetylates HIF1alpha and HIF2alpha to modulate hypoxia 
        responses.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect through deacetylation of HIF transcription 
        factors. One of many substrates of SIRT1.
  - term:
      id: GO:0141208
      label: NAD-dependent protein lysine delactylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000116
    review:
      summary: SIRT1 may have delactylase activity in addition to its primary 
        deacetylase function. IDA evidence from PMID:38512451.
      action: ACCEPT
      reason: Molecular function consistent with the broad deacylase activity of
        sirtuins.
  - term:
      id: GO:0160011
      label: NAD-dependent protein decrotonylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000116
    review:
      summary: SIRT1 has decrotonylase activity in addition to deacetylase 
        activity. IDA evidence from PMID:28497810.
      action: ACCEPT
      reason: Molecular function consistent with the broad deacylase activity of
        sirtuins. SIRT1 can remove various acyl modifications.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11672523
    review:
      summary: SIRT1 binds p53 (PMID:11672523). This protein binding annotation 
        is uninformative - the specific interaction with p53 is better captured 
        by the p53 binding annotation (GO:0002039).
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions (e.g. p53 
        binding, transcription factor binding).
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: hSIR2(SIRT1) functions as an NAD-dependent p53 
            deacetylase.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12006491
    review:
      summary: SIRT1 binds PML and p53 at PML nuclear bodies (PMID:12006491). 
        Generic protein binding is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:12006491
          supporting_text: Human SIR2 deacetylates p53 and antagonizes 
            PML/p53-induced cellular senescence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12535671
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: Human Sir2-related protein SIRT1 associates with the 
            bHLH repressors HES1 and HEY2 and is involved in HES1- and 
            HEY2-mediated transcriptional repression.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14976264
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:14976264
          supporting_text: Feb 19. Stress-dependent regulation of FOXO 
            transcription factors by the SIRT1 deacetylase.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15126506
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:15126506
          supporting_text: 2004 May 4. FOXO4 is acetylated upon peroxide stress 
            and deacetylated by the longevity protein hSir2(SIRT1).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15152190
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:15152190
          supporting_text: May 20. Modulation of NF-kappaB-dependent 
            transcription and cell survival by the SIRT1 deacetylase.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15175761
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:15175761
          supporting_text: Sirt1 promotes fat mobilization in white adipocytes 
            by repressing PPAR-gamma.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15205477
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:15205477
          supporting_text: Jun 17. Calorie restriction promotes mammalian cell 
            survival by inducing the SIRT1 deacetylase.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15220471
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:15220471
          supporting_text: Silent information regulator 2 potentiates 
            Foxo1-mediated transcription through its deacetylase activity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15632193
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:15632193
          supporting_text: 2005 Jan 4. SIRT1 deacetylation and repression of 
            p300 involves lysine residues 1020/1024 within the cell cycle 
            regulatory domain 1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15692560
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:15692560
          supporting_text: Suppression of FOXO1 activity by FHL2 through 
            SIRT1-mediated deacetylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16892051
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:16892051
          supporting_text: Interactions between E2F1 and SirT1 regulate 
            apoptotic response to DNA damage.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16998810
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:16998810
          supporting_text: SIRT1 interacts with p73 and suppresses p73-dependent
            transcriptional activity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17334224
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:17334224
          supporting_text: SIRT1 promotes DNA repair activity and deacetylation 
            of Ku70.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17612497
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:17612497
          supporting_text: SIRT1 regulates the function of the Nijmegen breakage
            syndrome protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17680780
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:17680780
          supporting_text: Sirt1 interacts with transducin-like enhancer of 
            split-1 to inhibit nuclear factor kappaB-mediated transcription.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17901049
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:17901049
          supporting_text: 2007 Sep 27. The direct involvement of SirT1 in 
            insulin-induced insulin receptor substrate-2 tyrosine 
            phosphorylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17936707
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:17936707
          supporting_text: SIRT1 deacetylates and positively regulates the 
            nuclear receptor LXR.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17964266
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:17964266
          supporting_text: Active regulator of SIRT1 cooperates with SIRT1 and 
            facilitates suppression of p53 activity.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18004385
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:18004385
          supporting_text: SIRT1 regulates the histone methyl-transferase 
            SUV39H1 during heterochromatin formation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18203716
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:18203716
          supporting_text: 2008 Jan 17. Regulation of WRN protein cellular 
            localization and enzymatic activities by SIRT1-mediated 
            deacetylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18235501
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:18235501
          supporting_text: DBC1 is a negative regulator of SIRT1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18235502
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:18235502
          supporting_text: Negative regulation of the deacetylase SIRT1 by DBC1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18296641
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:18296641
          supporting_text: A role for the NAD-dependent deacetylase Sirt1 in the
            regulation of autophagy.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18485871
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: Epigenetic control of rDNA loci in response to 
            intracellular energy status.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19047049
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19047049
          supporting_text: 2008 Dec 1. Hyaluronan-mediated CD44 interaction with
            p300 and SIRT1 regulates beta-catenin signaling and 
            NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL 
            gene expression and chemoresistance in breast tumor cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19188449
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19188449
          supporting_text: Feb 2. hSirT1-dependent regulation of the 
            PCAF-E2F1-p73 apoptotic pathway in response to DNA damage.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19236849
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19236849
          supporting_text: Carboxy-terminal phosphorylation of SIRT1 by protein 
            kinase CK2.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19343720
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19343720
          supporting_text: 'Identification and characterization of proteins interacting
            with SIRT1 and SIRT3: implications in the anti-aging and metabolic effects
            of sirtuins.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19478080
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19478080
          supporting_text: 2009 May 28. Enzymes in the NAD+ salvage pathway 
            regulate SIRT1 activity at target gene promoters.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19680552
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19680552
          supporting_text: CK2 is the regulator of SIRT1 substrate-binding 
            affinity, deacetylase activity and cellular response to DNA-damage.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19690166
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19690166
          supporting_text: 2009 Aug 18. Transcriptional corepressor SMILE 
            recruits SIRT1 to inhibit nuclear receptor estrogen receptor-related
            receptor gamma transactivation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19934257
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: Nov 24. SIRT1 deacetylates APE1 and regulates 
            cellular base excision repair.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19934264
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:19934264
          supporting_text: 'Nov 24. Reciprocal roles of SIRT1 and SKIP in the regulation
            of RAR activity: implication in the retinoic acid-induced neuronal differentiation
            of P19 cells.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20169165
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:20169165
          supporting_text: SIRT1 negatively regulates the mammalian target of 
            rapamycin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20375098
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:20375098
          supporting_text: Apr 7. Transcriptional corepressor SHP recruits SIRT1
            histone deacetylase to inhibit LRH-1 transactivation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20439735
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:20439735
          supporting_text: SIRT1 regulates Dishevelled proteins and promotes 
            transient and constitutive Wnt signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20660480
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:20660480
          supporting_text: Jul 25. SIRT1 is regulated by a PPAR{γ}-SIRT1 
            negative feedback loop associated with senescence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20670893
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:20670893
          supporting_text: SIRT1 regulates UV-induced DNA repair through 
            deacetylating XPA.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20817729
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:20817729
          supporting_text: 2010 Sep 3. SIRT1 deacetylates and inhibits SREBP-1C 
            activity in regulation of hepatic lipid metabolism.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21081649
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21081649
          supporting_text: Nov 16. SIRT2 regulates NF-κB dependent gene 
            expression through deacetylation of p65 Lys310.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21241768
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21241768
          supporting_text: Phosphoinositide 3-kinase as a novel functional 
            target for the regulation of the insulin signaling pathway by SIRT1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21245319
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21245319
          supporting_text: Methyltransferase Set7/9 regulates p53 activity by 
            interacting with Sirtuin 1 (SIRT1).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21471201
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21471201
          supporting_text: 2011 Apr 6. Cancer cell survival following DNA 
            damage-mediated premature senescence is regulated by mammalian 
            target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21555002
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21555002
          supporting_text: EVI1 up-regulates the stress responsive gene SIRT1 
            which triggers deacetylation and degradation of EVI1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21698133
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21698133
          supporting_text: 2011 Jun 16. SIRT1 promotes N-Myc oncogenesis through
            a positive feedback loop involving the effects of MKP3 and ERK on 
            N-Myc protein stability.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21775285
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21775285
          supporting_text: The deacetylase SIRT1 promotes membrane localization 
            and activation of Akt and PDK1 during tumorigenesis and cardiac 
            hypertrophy.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21807113
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21807113
          supporting_text: Sirt1 deacetylates c-Myc and promotes c-Myc/Max 
            association.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21890893
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21890893
          supporting_text: Sep 2. SIRT1 links CIITA deacetylation to MHC II 
            activation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21909281
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21909281
          supporting_text: 2011 Sep 1. The evolutionarily conserved longevity 
            determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate 
            DAF-16/FOXO.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21947282
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21947282
          supporting_text: Sep 26. SIRT1 deacetylates the DNA methyltransferase 
            1 (DNMT1) protein and alters its activities.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21968188
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21968188
          supporting_text: 2011 Sep 29. p53 deacetylation by SIRT1 decreases 
            during protein kinase CKII downregulation-mediated cellular 
            senescence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22094255
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:22094255
          supporting_text: Oxidative damage targets complexes containing DNA 
            methyltransferases, SIRT1, and polycomb members to promoter CpG 
            Islands.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22169038
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:22169038
          supporting_text: Dec 8. SIRT1 activates MAO-A in the brain to mediate 
            anxiety and exploratory drive.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22190034
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:22190034
          supporting_text: Global landscape of HIV-human protein complexes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22510882
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:22510882
          supporting_text: Novel repressor regulates insulin sensitivity through
            interaction with Foxo1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22863012
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:22863012
          supporting_text: Brown remodeling of white adipose tissue by 
            SirT1-dependent deacetylation of Pparγ.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24681097
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:24681097
          supporting_text: 2014 Mar 26. AROS has a context-dependent effect on 
            SIRT1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25751424
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:25751424
          supporting_text: Mar 9. NAD(+)-SIRT1 control of H3K4 trimethylation 
            through circadian deacetylation of MLL1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31403225
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:31403225
          supporting_text: Aug 12. The interactome of KRAB zinc finger proteins 
            reveals the evolutionary history of their functional 
            diversification.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32761762
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:32761762
          supporting_text: CSAG2 is a cancer-specific activator of SIRT1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 represses RNA Pol II transcription through histone 
        deacetylation and deacetylation of transcription factors.
      action: KEEP_AS_NON_CORE
      reason: Represents downstream transcriptional regulation rather than a
        singular core function.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "Gal4-SirT1 expression resulted in the deacetylation of
            H4-K16 and H3-K9, recruitment of H1 within the promoter vicinity, drastically
            reduced reporter expression"
  - term:
      id: GO:0000720
      label: pyrimidine dimer repair by nucleotide-excision repair
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 participates in DNA repair processes through deacetylation 
        of repair proteins. This is one of many DNA damage response roles 
        mediated by SIRT1 deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of SIRT1 deacetylase activity on DNA repair 
        proteins. SIRT1 contributes to DNA repair but this specific pathway is 
        not its core function.
  - term:
      id: GO:0000731
      label: DNA synthesis involved in DNA repair
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 participates in DNA repair processes through deacetylation 
        of repair proteins. This is one of many DNA damage response roles 
        mediated by SIRT1 deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of SIRT1 deacetylase activity on DNA repair 
        proteins. SIRT1 contributes to DNA repair but this specific pathway is 
        not its core function.
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 localizes to chromatin where it functions as a histone 
        deacetylase. Core localization consistent with its primary enzymatic 
        function.
      action: ACCEPT
      reason: Core localization. SIRT1 functions at chromatin to deacetylate 
        histones and regulate transcription.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
  - term:
      id: GO:0000792
      label: heterochromatin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 promotes heterochromatin formation through histone 
        deacetylation. Core localization consistent with its primary function in
        chromatin silencing.
      action: ACCEPT
      reason: Core localization. SIRT1 promotes facultative heterochromatin 
        formation through deacetylation of H4K16 and H3K9.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "We propose a model for SirT1-mediated heterochromatin
            formation that includes deacetylation of histone tails, recruitment and
            deacetylation of histone H1, and spreading of hypomethylated H3-K79 with
            resultant silencing."
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 does not have intrinsic sequence-specific DNA binding 
        activity. It is recruited to promoters through interactions with 
        transcription factors rather than direct DNA sequence recognition.
      action: REMOVE
      reason: SIRT1 lacks intrinsic sequence-specific DNA binding. It is a 
        deacetylase that is recruited to chromatin through protein-protein 
        interactions, not DNA sequence recognition.
  - term:
      id: GO:0001525
      label: angiogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 affects angiogenesis through deacetylation of HIF and FOXO 
        transcription factors. This is a downstream pleiotropic effect of its 
        broad deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect. SIRT1 modulates angiogenesis 
        through its effects on transcription factors but this is not its core 
        function.
  - term:
      id: GO:0001678
      label: intracellular glucose homeostasis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates glucose homeostasis through deacetylation of 
        PGC-1alpha, FOXO factors, and other metabolic regulators. NAD+ 
        dependence links SIRT1 activity to metabolic state.
      action: KEEP_AS_NON_CORE
      reason: Important downstream metabolic effect of SIRT1 deacetylase 
        activity. SIRT1 functions as a metabolic sensor through NAD+ dependence 
        but glucose homeostasis per se is not its core function.
  - term:
      id: GO:0002039
      label: p53 binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 directly binds p53 and deacetylates its C-terminal K382 
        residue. Well-established substrate interaction demonstrated in multiple
        studies (PMID:11672523, PMID:12006491).
      action: ACCEPT
      reason: Core substrate interaction. p53 is a major non-histone substrate 
        of SIRT1. Binding is required for deacetylation of p53 K382.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: "the protein product of the gene hSIR2(SIRT1), the human
            homolog of the S. cerevisiae Sir2 protein known to be involved in cell
            aging and in the response to DNA damage, binds and deacetylates the p53
            protein with a specificity for its C-terminal Lys382 residue"
        - reference_id: PMID:12006491
          supporting_text: "SIRT1 binds and deacetylates p53, a component of PML nuclear
            bodies, and it can repress p53-mediated transactivation."
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 is primarily a transcriptional corepressor through histone 
        deacetylation. However, in some contexts deacetylation of specific 
        transcription factors can enhance their activity. This is a minor 
        function compared to corepressor activity.
      action: KEEP_AS_NON_CORE
      reason: Context-dependent function. SIRT1 is predominantly a corepressor 
        but can have coactivator effects in specific contexts. Not the core 
        function.
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 functions as a transcriptional corepressor through histone 
        deacetylation and deacetylation of transcription factors. Core molecular
        function well-supported by phylogenetic inference and experimental 
        evidence (PMID:15469825, PMID:20955178).
      action: ACCEPT
      reason: Core molecular function. SIRT1 mediates transcriptional repression
        through heterochromatin formation and deacetylation of transcription 
        factors.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "We propose a model for SirT1-mediated heterochromatin
            formation that includes deacetylation of histone tails, recruitment and
            deacetylation of histone H1, and spreading of hypomethylated H3-K79 with
            resultant silencing."
  - term:
      id: GO:0004857
      label: enzyme inhibitor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 is an enzyme (deacetylase) itself, not primarily an enzyme 
        inhibitor. While deacetylation can modulate enzyme activity, this is an 
        indirect effect. This annotation is misleading.
      action: REMOVE
      reason: Misleading annotation. SIRT1 is a deacetylase enzyme, not an 
        enzyme inhibitor. Any effects on other enzyme activities are indirect 
        consequences of its deacetylation activity.
  - term:
      id: GO:0006642
      label: triglyceride mobilization
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates lipid metabolism through deacetylation of SREBP 
        and other lipid metabolism transcription factors. This is a downstream 
        pleiotropic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. SIRT1 modulates lipid metabolism 
        through transcription factor deacetylation but this is not its core 
        function.
  - term:
      id: GO:0007623
      label: circadian rhythm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can deacetylate circadian clock components but this is one 
        of many substrates. Clock regulation is not the core function.
      action: MARK_AS_OVER_ANNOTATED
      reason: SIRT1 deacetylates many transcription factors including clock 
        proteins. This represents an over-annotation based on one substrate 
        class rather than the core NAD-dependent deacetylase function.
  - term:
      id: GO:0008630
      label: intrinsic apoptotic signaling pathway in response to DNA damage
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 modulates DNA damage-induced apoptosis primarily through 
        deacetylation of p53, suppressing its pro-apoptotic activity 
        (PMID:11672523). This is a downstream effect of SIRT1 deacetylase 
        activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of SIRT1 deacetylase activity on p53 and other 
        apoptotic regulators. Apoptosis regulation is not SIRT1's core function.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: "Expression of wild-type hSir2 in human cells reduces the
            transcriptional activity of p53. In contrast, expression of a catalytically
            inactive hSir2 protein potentiates p53-dependent apoptosis and radiosensitivity."
  - term:
      id: GO:0009267
      label: cellular response to starvation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 is activated by increased NAD+/NADH ratio during starvation
        and mediates metabolic adaptations through deacetylation of PGC-1alpha, 
        FOXO, and other metabolic regulators (PMID:18485871). This is an 
        important metabolic sensor function.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic response. SIRT1 NAD+ dependence makes it a 
        metabolic sensor but starvation response per se is not its core 
        function.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: "a change in the NAD(+)/NADH ratio induced by reduction
            of energy status could activate SIRT1, leading to deacetylation of histone
            H3 and dimethylation at Lys9 by SUV39H1, thus establishing silent chromatin"
  - term:
      id: GO:0010875
      label: positive regulation of cholesterol efflux
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates cholesterol metabolism through deacetylation of 
        LXR and other cholesterol metabolism regulators. This is a downstream 
        pleiotropic metabolic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. SIRT1 modulates cholesterol 
        metabolism through transcription factor deacetylation but this is not 
        its core function.
  - term:
      id: GO:0010883
      label: regulation of lipid storage
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates lipid storage through deacetylation of SREBP and 
        other lipid metabolism transcription factors. This is a downstream 
        pleiotropic metabolic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. SIRT1 modulates lipid storage through
        transcription factor deacetylation but this is not its core function.
  - term:
      id: GO:0010906
      label: regulation of glucose metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates glucose metabolism through deacetylation of 
        PGC-1alpha, FOXO factors, and other metabolic regulators. NAD+ 
        dependence links SIRT1 activity to metabolic state.
      action: KEEP_AS_NON_CORE
      reason: Important downstream metabolic effect of SIRT1 deacetylase 
        activity but glucose metabolism per se is not its core function.
  - term:
      id: GO:0016239
      label: positive regulation of macroautophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates autophagy through deacetylation of 
        autophagy-related proteins and FOXO transcription factors. This is a 
        downstream effect of SIRT1 deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect. SIRT1 modulates autophagy through protein 
        deacetylation but autophagy regulation is not its core function.
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: NAD-dependent histone deacetylase activity is the core enzymatic 
        function of SIRT1. Well-demonstrated through multiple experimental 
        studies (PMID:15469825, PMID:12006491).
      action: ACCEPT
      reason: Core molecular function. This is the primary enzymatic activity of
        SIRT1 on histones.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
  - term:
      id: GO:0019213
      label: deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Deacetylase activity is the core enzymatic function of SIRT1. 
        This is a broader parent term; more specific NAD-dependent protein 
        lysine deacetylase activity annotations are preferred.
      action: ACCEPT
      reason: Core molecular function. SIRT1 is an NAD-dependent deacetylase. 
        This general term is correct but less informative than more specific 
        deacetylase annotations.
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 binds multiple enzymes and enzyme complexes.
      action: ACCEPT
      reason: Enzyme binding is supported by multiple interaction studies.
  - term:
      id: GO:0019904
      label: protein domain specific binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 interacts with specific protein domains but this generic 
        annotation is not informative about the specific interactions.
      action: REMOVE
      reason: Generic protein domain binding annotation is uninformative. More 
        specific annotations for particular domain interactions are preferred.
  - term:
      id: GO:0030225
      label: macrophage differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 affects macrophage differentiation through deacetylation of
        transcription factors. This is a downstream pleiotropic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream pleiotropic effect on immune cell differentiation. Not 
        the core function of SIRT1.
  - term:
      id: GO:0030512
      label: negative regulation of transforming growth factor beta receptor 
        signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can modulate TGF-beta signaling through deacetylation of 
        SMAD proteins. This is a downstream pleiotropic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling effect through transcription factor 
        deacetylation. Not the core function of SIRT1.
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 deacetylates XBP1s and modulates the UPR (PMID:20955178). 
        This is a downstream effect of SIRT1 deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect through XBP1s deacetylation. UPR regulation is 
        not the core function of SIRT1.
      supported_by:
        - reference_id: PMID:20955178
          supporting_text: "SIRT1 deacetylates XBP1s and inhibits its transcriptional
            activity."
  - term:
      id: GO:0031393
      label: negative regulation of prostaglandin biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can affect prostaglandin biosynthesis through deacetylation
        of inflammatory regulators like NF-kB. This is a downstream pleiotropic 
        effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream anti-inflammatory effect through transcription factor 
        deacetylation. Not the core function of SIRT1.
  - term:
      id: GO:0031648
      label: protein destabilization
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 deacetylation can promote protein destabilization and 
        degradation of some substrates (e.g., PER2). This is a downstream effect
        of deacetylase activity.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect on specific substrates. Protein destabilization 
        per se is not SIRT1's core function.
  - term:
      id: GO:0032007
      label: negative regulation of TOR signaling
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can modulate mTOR signaling through deacetylation of 
        pathway components. This is a downstream metabolic signaling effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling effect. mTOR regulation is not the core 
        function of SIRT1.
  - term:
      id: GO:0032868
      label: response to insulin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 modulates insulin sensitivity through deacetylation of IRS 
        proteins and insulin signaling components. Downstream metabolic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. Insulin response is not the core 
        function of SIRT1.
  - term:
      id: GO:0032922
      label: circadian regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 modulates circadian clock components through deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Circadian regulation is a downstream outcome of SIRT1 activity.
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 functions in various protein complexes including the eNoSC 
        complex at rDNA loci (PMID:18485871). This is a generic localization 
        annotation.
      action: ACCEPT
      reason: SIRT1 functions within protein complexes. This generic annotation 
        is consistent with its participation in eNoSC and other chromatin 
        regulatory complexes.
  - term:
      id: GO:0033210
      label: leptin-mediated signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can modulate leptin signaling in the hypothalamus. This is 
        a downstream metabolic signaling effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling effect in specific tissues. Leptin signaling 
        is not the core function of SIRT1.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Protein lysine deacetylase activity is the core enzymatic 
        function of SIRT1. SIRT1 deacetylates histones and many non-histone 
        proteins at lysine residues (PMID:15469825, PMID:11672523).
      action: ACCEPT
      reason: Core molecular function. This is the primary enzymatic activity of
        SIRT1.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: "the protein product of the gene hSIR2(SIRT1)...binds and
            deacetylates the p53 protein with a specificity for its C-terminal Lys382
            residue"
  - term:
      id: GO:0034391
      label: regulation of smooth muscle cell apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can modulate smooth muscle cell apoptosis through 
        deacetylation of p53 and other apoptotic regulators. This is a 
        downstream pleiotropic effect in specific cell types.
      action: KEEP_AS_NON_CORE
      reason: Downstream cell type-specific effect. Smooth muscle cell apoptosis
        regulation is not the core function of SIRT1.
  - term:
      id: GO:0035356
      label: intracellular triglyceride homeostasis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates triglyceride metabolism through deacetylation of 
        SREBP and other metabolic transcription factors. Downstream metabolic 
        effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. Triglyceride homeostasis is not the 
        core function of SIRT1.
  - term:
      id: GO:0035358
      label: regulation of peroxisome proliferator activated receptor signaling 
        pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can modulate PPAR signaling through deacetylation of PPAR 
        coactivators like PGC-1alpha. Downstream metabolic signaling effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic signaling effect. PPAR signaling regulation 
        is not the core function of SIRT1.
  - term:
      id: GO:0042632
      label: cholesterol homeostasis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates cholesterol metabolism through deacetylation of 
        LXR and other cholesterol metabolism regulators. Downstream metabolic 
        effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. Cholesterol homeostasis is not the 
        core function of SIRT1.
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 generally suppresses apoptosis through p53 deacetylation 
        but can have context-dependent pro-apoptotic effects. Downstream effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream context-dependent effect on apoptosis. Apoptosis 
        regulation is not the core function of SIRT1.
  - term:
      id: GO:0044321
      label: response to leptin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can modulate leptin signaling in the hypothalamus. 
        Downstream metabolic signaling effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic signaling effect. Leptin response is not the 
        core function of SIRT1.
  - term:
      id: GO:0045599
      label: negative regulation of fat cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 inhibits adipogenesis through deacetylation of PPAR-gamma 
        and other adipogenic transcription factors. Downstream metabolic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect on adipocyte differentiation. Not the 
        core function of SIRT1.
  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 promotes gluconeogenesis through deacetylation and 
        activation of PGC-1alpha and FOXO1. Well-supported metabolic function.
      action: KEEP_AS_NON_CORE
      reason: Important downstream metabolic effect through PGC-1alpha/FOXO1 
        deacetylation. Not the core function but a well-established metabolic 
        role.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 is predominantly a transcriptional corepressor but can 
        positively regulate transcription of some genes through effects on 
        specific transcription factors. Context-dependent effect.
      action: KEEP_AS_NON_CORE
      reason: Secondary function. SIRT1 is primarily a corepressor but has 
        context-dependent coactivator effects on some promoters.
  - term:
      id: GO:0046969
      label: histone H3K9 deacetylase activity, NAD-dependent
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: H3K9 deacetylation is a core histone modification activity of 
        SIRT1. Well-demonstrated in PMID:15469825.
      action: ACCEPT
      reason: Core molecular function. H3K9 deacetylation is one of SIRT1's 
        primary histone substrate specificities.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
  - term:
      id: GO:0050872
      label: white fat cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 inhibits white adipocyte differentiation through effects on
        PPAR-gamma and other adipogenic regulators. Downstream metabolic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect on adipocyte differentiation. Not the 
        core function of SIRT1.
  - term:
      id: GO:0051152
      label: positive regulation of smooth muscle cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 affects smooth muscle cell differentiation through 
        transcription factor deacetylation. Downstream pleiotropic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream cell type-specific effect. Not the core function of 
        SIRT1.
  - term:
      id: GO:0051897
      label: positive regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can modulate PI3K/AKT signaling through effects on insulin 
        signaling and other pathways. Downstream signaling effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling effect. PI3K/AKT regulation is not the core 
        function of SIRT1.
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can negatively modulate PI3K/AKT signaling in some 
        contexts. Context-dependent downstream signaling effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream context-dependent signaling effect. PI3K/AKT regulation
        is not the core function of SIRT1.
  - term:
      id: GO:0055089
      label: fatty acid homeostasis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates fatty acid metabolism through deacetylation of 
        SREBP and other lipid metabolism transcription factors. Downstream 
        metabolic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. Fatty acid homeostasis is not the 
        core function of SIRT1.
  - term:
      id: GO:0060907
      label: positive regulation of macrophage cytokine production
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 modulates macrophage cytokine production through NF-kB 
        deacetylation and other inflammatory regulators. Downstream immune 
        effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream immune/inflammatory effect. Macrophage cytokine 
        regulation is not the core function of SIRT1.
  - term:
      id: GO:0070857
      label: regulation of bile acid biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 regulates bile acid metabolism through deacetylation of FXR
        and other bile acid metabolism regulators. Downstream metabolic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect. Bile acid regulation is not the core 
        function of SIRT1.
  - term:
      id: GO:0071479
      label: cellular response to ionizing radiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 modulates DNA damage response through deacetylation of p53 
        and other DNA repair/checkpoint proteins. Downstream stress response 
        effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream stress response effect through p53 and DNA repair 
        protein deacetylation. Not the core function of SIRT1.
  - term:
      id: GO:0090335
      label: regulation of brown fat cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 affects brown adipocyte differentiation through effects on 
        PGC-1alpha and other thermogenic regulators. Downstream metabolic 
        effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect on adipocyte differentiation. Not the 
        core function of SIRT1.
  - term:
      id: GO:0106231
      label: NAD-dependent protein-lysine depropionylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: SIRT1 can remove propionyl groups from lysine residues in 
        addition to acetyl groups. Minor enzymatic activity compared to 
        deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Secondary enzymatic activity. Depropionylation is a minor activity
        compared to the primary deacetylase function.
  - term:
      id: GO:1902166
      label: negative regulation of intrinsic apoptotic signaling pathway in 
        response to DNA damage by p53 class mediator
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 suppresses p53-mediated apoptosis through deacetylation of 
        p53 K382 (PMID:11672523). Well-established downstream effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of SIRT1 deacetylase activity on p53. Apoptosis 
        regulation is not SIRT1's core function but this is a well-supported 
        effect.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: "Expression of wild-type hSir2 in human cells reduces the
            transcriptional activity of p53. In contrast, expression of a catalytically
            inactive hSir2 protein potentiates p53-dependent apoptosis and radiosensitivity."
  - term:
      id: GO:1902237
      label: positive regulation of endoplasmic reticulum stress-induced 
        intrinsic apoptotic signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 can modulate ER stress-induced apoptosis through effects on
        XBP1s and other UPR regulators (PMID:20955178). Context-dependent 
        effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream context-dependent effect on ER stress apoptosis. Not 
        the core function of SIRT1.
      supported_by:
        - reference_id: PMID:20955178
          supporting_text: "Sirt1-/- MEFs display a greater resistance to ER-stress-induced
            apoptotic cell death compared with Sirt1+/+ MEFs."
  - term:
      id: GO:1904179
      label: positive regulation of adipose tissue development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 affects adipose tissue development through effects on 
        PPAR-gamma and other adipogenic regulators. Context-dependent downstream
        metabolic effect.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic effect on adipose development. Not the core 
        function of SIRT1.
  - term:
      id: GO:1990841
      label: promoter-specific chromatin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: SIRT1 is recruited to specific promoters through interactions 
        with transcription factors. Core localization related to its 
        transcriptional regulatory function.
      action: ACCEPT
      reason: Core localization. SIRT1 binds chromatin at specific promoters to 
        regulate transcription through histone deacetylation.
  - term:
      id: GO:2000111
      label: positive regulation of macrophage apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Annotation indicates SIRT1 can influence macrophage apoptosis
        through deacetylation of regulatory factors in immune contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream immune regulation rather than a core function; keep
        as non-core despite indirect support.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: SIRT1 localizes to nuclear compartments including the
        nucleoplasm.
      action: ACCEPT
      reason: Consistent with nuclear localization shown in immunostaining
        studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Mitochondrial localization for full-length SIRT1 is not clearly
        supported here.
      action: UNDECIDED
      reason: Evidence may be context- or isoform-specific; requires
        confirmation.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: SIRT1 localizes to the cytosol as well as the nucleus.
      action: ACCEPT
      reason: Immunostaining shows cytoplasmic localization.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0000183
      label: rDNA heterochromatin formation
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-427359
    review:
      summary: SIRT1 in eNoSC promotes rRNA gene silencing via histone
        modification.
      action: ACCEPT
      reason: Reactome summary describes eNoSC-mediated repression of rRNA
        genes.
      supported_by:
        - reference_id: Reactome:R-HSA-427359
          supporting_text: Deacetylation and methylation of histone H3 in the
            chromatin of a rRNA gene by eNoSC causes reduced expression of the
            gene.
        - reference_id: Reactome:R-HSA-427359
          supporting_text: eNoSC comprises Nucleomethylin (NML), SIRT1, and
            the histone methylase SUV39H1 (Murayama et al. 2008).
  - term:
      id: GO:1900034
      label: regulation of cellular response to heat
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3371453
    review:
      summary: SIRT1 participates in heat shock response regulation via HSF1
        deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Pathway-level regulatory effect rather than core function.
      supported_by:
        - reference_id: Reactome:R-HSA-3371467
          supporting_text: Sirtuin 1 (SIRT1) functions as a NAD(+)-dependent
            deacetylase, which regulates the heat shock response through
            deacetylation of HSF1 at Lys80.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3371467
    review:
      summary: SIRT1 functions as a NAD-dependent deacetylase in the HSF1 heat
        shock pathway.
      action: ACCEPT
      reason: Core enzymatic activity supported in Reactome summary.
      supported_by:
        - reference_id: Reactome:R-HSA-3371467
          supporting_text: Sirtuin 1 (SIRT1) functions as a NAD(+)-dependent
            deacetylase, which regulates the heat shock response through
            deacetylation of HSF1 at Lys80.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9620532
    review:
      summary: SIRT1 deacetylates FOXO3 as an NAD-dependent histone
        deacetylase.
      action: ACCEPT
      reason: Reactome summary documents FOXO3 deacetylation by SIRT1.
      supported_by:
        - reference_id: Reactome:R-HSA-9620532
          supporting_text: SIRT1, an NAD-dependent histone deacetylase,
            deacetylates FOXO3.
  - term:
      id: GO:0000183
      label: rDNA heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:18485871
    review:
      summary: eNoSC containing SIRT1 establishes silent chromatin at rDNA
        loci.
      action: ACCEPT
      reason: Supported by the eNoSC complex and rDNA chromatin silencing.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: eNoSC contains Nucleomethylin, which binds histone
            H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1
            and SUV39H1.
        - reference_id: PMID:18485871
          supporting_text: thus establishing silent chromatin in the rDNA
            locus.
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: PMID:18485871
    review:
      summary: SIRT1 participates in rDNA locus regulation within the
        nucleolar context.
      action: KEEP_AS_NON_CORE
      reason: Context-specific localization associated with rDNA regulation.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: eNoSC contains Nucleomethylin, which binds histone
            H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1
            and SUV39H1.
  - term:
      id: GO:0042149
      label: cellular response to glucose starvation
    evidence_type: IMP
    original_reference_id: PMID:18485871
    review:
      summary: This study links energy status to rRNA transcription, but
        glucose-specific starvation is not explicit.
      action: MARK_AS_OVER_ANNOTATED
      reason: The term is too specific relative to the evidence presented.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: Furthermore, eNoSC promotes restoration of energy
            balance by limiting rRNA transcription, thus protecting cells from
            energy deprivation-dependent apoptosis.
  - term:
      id: GO:0045786
      label: negative regulation of cell cycle
    evidence_type: IMP
    original_reference_id: PMID:18485871
    review:
      summary: Negative regulation of cell cycle is not described in the
        PMID:18485871 abstract.
      action: UNDECIDED
      reason: Insufficient evidence in this reference for cell cycle
        regulation.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: SIRT1 and SUV39H1 are required for energy-dependent
            transcriptional repression
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IMP
    original_reference_id: PMID:18485871
    review:
      summary: SIRT1 and SUV39H1 are required for energy-dependent
        transcriptional repression at rDNA loci.
      action: KEEP_AS_NON_CORE
      reason: Represents context-specific repression of rRNA transcription.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: SIRT1 and SUV39H1 are required for energy-dependent
            transcriptional repression
  - term:
      id: GO:0046015
      label: regulation of transcription by glucose
    evidence_type: IMP
    original_reference_id: PMID:18485871
    review:
      summary: The evidence discusses energy status broadly rather than
        glucose-specific transcriptional control.
      action: MARK_AS_OVER_ANNOTATED
      reason: Glucose-specific regulation is not explicit in the abstract.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: Furthermore, eNoSC promotes restoration of energy
            balance by limiting rRNA transcription, thus protecting cells from
            energy deprivation-dependent apoptosis.
  - term:
      id: GO:0097009
      label: energy homeostasis
    evidence_type: IMP
    original_reference_id: PMID:18485871
    review:
      summary: eNoSC limits rRNA transcription to restore energy balance.
      action: KEEP_AS_NON_CORE
      reason: Energy homeostasis is a downstream consequence of rDNA
        repression.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: Furthermore, eNoSC promotes restoration of energy
            balance by limiting rRNA transcription, thus protecting cells from
            energy deprivation-dependent apoptosis.
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: IDA
    original_reference_id: PMID:20955178
    review:
      summary: SIRT1 represses XBP1s transcriptional activity via
        deacetylation.
      action: ACCEPT
      reason: Corepressor activity is supported by inhibition of XBP1s.
      supported_by:
        - reference_id: PMID:20955178
          supporting_text: SIRT1 deacetylates XBP1s and inhibits its
            transcriptional activity
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IDA
    original_reference_id: PMID:20955178
    review:
      summary: SIRT1 modulates the unfolded protein response through XBP1s
        deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Represents a pathway-specific regulatory role.
      supported_by:
        - reference_id: PMID:20955178
          supporting_text: Deficiency of SIRT1 enhances XBP1s-mediated
            luciferase reporter activity in HEK (human embryonic kidney)-293
            cells
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:20955178
    review:
      summary: SIRT1 deacetylates XBP1s as a lysine deacetylase.
      action: ACCEPT
      reason: Direct deacetylation of XBP1s supports this activity.
      supported_by:
        - reference_id: PMID:20955178
          supporting_text: In the present study, we demonstrate that XBP1s is
            a target of acetylation and deacetylation mediated by p300 and
            SIRT1 (sirtuin 1) respectively
  - term:
      id: GO:0004407
      label: histone deacetylase activity
    evidence_type: EXP
    original_reference_id: PMID:18485871
    review:
      summary: SIRT1 contributes to histone deacetylation during rDNA
        silencing.
      action: ACCEPT
      reason: Core enzymatic activity within the eNoSC complex.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: SIRT1 and SUV39H1 are required for energy-dependent
            transcriptional repression
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9825772
    review:
      summary: SIRT1 deacetylates HINT1, consistent with protein lysine
        deacetylase activity.
      action: ACCEPT
      reason: Reactome summary documents SIRT1-dependent deacetylation.
      supported_by:
        - reference_id: Reactome:R-HSA-9825772
          supporting_text: Deacetylation at these sites by SIRT1 promotes the
            interaction between MITF and HINT1
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:11672523
    review:
      summary: SIRT1 reduces p53 transcriptional activity via deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Represents a downstream regulatory effect on p53 target genes.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: Expression of wild-type hSir2 in human cells
            reduces the transcriptional activity of p53
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IMP
    original_reference_id: PMID:11672523
    review:
      summary: SIRT1 deacetylates p53 in an NAD-dependent manner.
      action: ACCEPT
      reason: Core enzymatic activity supported by direct deacetylation of
        p53.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: binds and deacetylates the p53 protein with a
            specificity for its C-terminal Lys382 residue
  - term:
      id: GO:0140416
      label: transcription regulator inhibitor activity
    evidence_type: IDA
    original_reference_id: PMID:11672523
    review:
      summary: SIRT1 represses p53-mediated transcription; a corepressor term
        better captures this activity.
      action: MODIFY
      reason: Use transcription corepressor activity for this function instead
        of a generic inhibitor term.
      proposed_replacement_terms:
        - id: GO:0003714
          label: transcription corepressor activity
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: Expression of wild-type hSir2 in human cells
            reduces the transcriptional activity of p53
  - term:
      id: GO:0008047
      label: enzyme activator activity
    evidence_type: IDA
    original_reference_id: PMID:18203716
    review:
      summary: SIRT1 reverses WRN acetylation effects on enzymatic activities
        via deacetylation rather than acting as a classical enzyme activator.
      action: MARK_AS_OVER_ANNOTATED
      reason: The mechanism is deacetylation, not direct enzyme activation.
      supported_by:
        - reference_id: PMID:18203716
          supporting_text: WRN acetylation decreases its helicase and
            exonuclease activities, and SIRT1 can reverse this effect.
  - term:
      id: GO:0035331
      label: negative regulation of hippo signaling
    evidence_type: IDA
    original_reference_id: PMID:38512451
    review:
      summary: SIRT1 delactylates YAP, counteracting lactylation-linked Hippo
        pathway activation.
      action: KEEP_AS_NON_CORE
      reason: Context-specific modulation of YAP activity rather than a core
        SIRT1 function.
      supported_by:
        - reference_id: PMID:38512451
          supporting_text: overexpression of SIRT1, but not of other members of
            this family, substantially reduced the lactylation levels of YAP
  - term:
      id: GO:0141208
      label: NAD-dependent protein lysine delactylase activity
    evidence_type: IDA
    original_reference_id: PMID:38512451
    review:
      summary: SIRT1 removes lactylation from YAP and TEAD1 peptides in vitro.
      action: ACCEPT
      reason: Direct delactylation activity is demonstrated with purified
        enzyme.
      supported_by:
        - reference_id: PMID:38512451
          supporting_text: purified SIRT1, but not the H363Y mutant, eliminated
            lactylation of synthetic peptides of both YAP K90lac and TEAD1
            K108lac
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:20203304
    review:
      summary: SIRT1 can repress RNA polymerase II transcription through
        deacetylation of transcription factors; this is a downstream effect.
      action: KEEP_AS_NON_CORE
      reason: Transcriptional repression is a contextual outcome of SIRT1
        deacetylase activity rather than a core function.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: Expression of wild-type hSir2 in human cells
            reduces the transcriptional activity of p53
  - term:
      id: GO:0032436
      label: positive regulation of proteasomal ubiquitin-dependent protein 
        catabolic process
    evidence_type: IMP
    original_reference_id: PMID:20203304
    review:
      summary: SIRT1 promotes proteasome-mediated degradation of LKB1.
      action: KEEP_AS_NON_CORE
      reason: Represents substrate-specific regulation of protein stability.
      supported_by:
        - reference_id: PMID:20203304
          supporting_text: SIRT1 antagonized LKB1-dependent AMPK activation
            through promoting the deacetylation, ubiquitination and
            proteasome-mediated degradation of LKB1.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IMP
    original_reference_id: PMID:20203304
    review:
      summary: SIRT1 deacetylates LKB1 as a protein lysine deacetylase.
      action: ACCEPT
      reason: Direct deacetylation is reported.
      supported_by:
        - reference_id: PMID:20203304
          supporting_text: SIRT1 antagonized LKB1-dependent AMPK activation
            through promoting the deacetylation, ubiquitination and
            proteasome-mediated degradation of LKB1.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:22918831
    review:
      summary: NAD-dependent protein lysine deacetylase activity is the core
        enzymatic function of SIRT1.
      action: ACCEPT
      reason: Core molecular function supported by multiple experimental
        studies.
      supported_by:
        - reference_id: PMID:22918831
          supporting_text: Autoacetylation of the MYST lysine acetyltransferase MOF protein.
        - reference_id: PMID:15692560
          supporting_text: SIRT1, a mammalian homolog of yeast Sir2, bound to
            and deacetylated FOXO1 and inhibited its transcriptional activity.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:17505061
    review:
      summary: SIRT1 is required for androgen antagonist-mediated
        transcriptional repression.
      action: KEEP_AS_NON_CORE
      reason: Context-specific repression in androgen receptor signaling.
      supported_by:
        - reference_id: PMID:17505061
          supporting_text: is required for androgen antagonist-mediated
            transcriptional repression and growth suppression
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: IMP
    original_reference_id: PMID:17505061
    review:
      summary: SIRT1 acts as a transcriptional corepressor in AR antagonist
        responses.
      action: ACCEPT
      reason: Direct evidence for corepressor function at AR-responsive
        promoters.
      supported_by:
        - reference_id: PMID:17505061
          supporting_text: androgen receptor (AR) recruits SIRT1 and nuclear
            receptor corepressor to AR-responsive promoters and deacetylates
            histone H3 locally
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:12006491
    review:
      summary: SIRT1 is an NAD-dependent histone deacetylase.
      action: ACCEPT
      reason: Histone deacetylase activity is supported by multiple SIRT1
        studies.
      supported_by:
        - reference_id: PMID:12006491
          supporting_text: SIRT1 binds and deacetylates p53
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: SIRT1 is an NAD-dependent histone deacetylase that deacetylates
        H4K16 and H3K9.
      action: ACCEPT
      reason: Core enzymatic activity in chromatin regulation.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0032041
      label: histone H3K14 deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: SIRT1 is an NAD-dependent histone deacetylase with H3-directed
        activity.
      action: ACCEPT
      reason: Histone deacetylase activity is well supported and H3K14
        specificity is consistent with SIRT1 histone targeting.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:20027304
    review:
      summary: SIRT1 is an NAD-dependent protein deacetylase.
      action: ACCEPT
      reason: Core molecular function supported by this study.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 is a NAD-dependent deacetylase that regulates
            a variety of pathways
  - term:
      id: GO:0046969
      label: histone H3K9 deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: SIRT1 deacetylates histone H3K9 in vitro.
      action: ACCEPT
      reason: Core histone substrate supported by biochemical evidence.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0046970
      label: histone H4K16 deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: SIRT1 deacetylates histone H4K16 in vitro.
      action: ACCEPT
      reason: Core histone substrate supported by biochemical evidence.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0140937
      label: histone H4K12 deacetylase activity, hydrolytic mechanism
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: H4K12 deacetylation is not described in the PMID:15469825
        abstract.
      action: UNDECIDED
      reason: Additional evidence is required to support H4K12 specificity.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0141050
      label: histone H3K deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:20027304
    review:
      summary: SIRT1 deacetylates histone H3 in cells.
      action: ACCEPT
      reason: Histone H3 is a demonstrated substrate in this study.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: resulting in selective activation of SIRT1, as
            measured by deacetylation of histone H3
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:29681526
    review:
      summary: Sirtuin deacetylase recruitment supports NAD-dependent protein
        lysine deacetylase activity.
      action: ACCEPT
      reason: The study references sirtuin deacetylase activity in the p53
        modification complex.
      supported_by:
        - reference_id: PMID:29681526
          supporting_text: Morn3, a cancer-testis antigen, recruits different
            PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to
            confer composite modifications on p53.
  - term:
      id: GO:1901797
      label: negative regulation of signal transduction by p53 class mediator
    evidence_type: IDA
    original_reference_id: PMID:29681526
    review:
      summary: p53 suppression is described but the specific SIRT1-dependent
        mechanism is not explicit.
      action: UNDECIDED
      reason: The abstract does not directly attribute p53 signal suppression
        to SIRT1.
      supported_by:
        - reference_id: PMID:29681526
          supporting_text: We found that Morn3, a cancer-testis antigen,
            recruits different PTM enzymes, such as sirtuin deacetylase and
            ubiquitin ligase, to confer composite modifications on p53.
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:16079181
    review:
      summary: SIRT1 shows in vitro deacetylase activity on histone H4 peptides.
      action: ACCEPT
      reason: The study reports SIRT1-specific histone deacetylase activity.
      supported_by:
        - reference_id: PMID:16079181
          supporting_text: SIRT1, but not the other two nuclear SIRT proteins,
            shows an in vitro deacetylase activity on histone H4 and p53
            peptides
  - term:
      id: GO:1990404
      label: NAD+-protein mono-ADP-ribosyltransferase activity
    evidence_type: TAS
    original_reference_id: PMID:17456799
    negated: true
    review:
      summary: Review notes that some sirtuins have ADP-ribosyltransferase
        activity but does not specify SIRT1.
      action: UNDECIDED
      reason: The reference does not provide SIRT1-specific evidence to support
        or refute this activity.
      supported_by:
        - reference_id: PMID:17456799
          supporting_text: Certain sirtuins have in addition an
            ADP-ribosyltransferase activity.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:32538779
    review:
      summary: SIRT1 deacetylates SIRT6 at K33 in the DNA damage response.
      action: ACCEPT
      reason: Direct deacetylation of a protein substrate is reported.
      supported_by:
        - reference_id: PMID:32538779
          supporting_text: SIRT1 deacetylates SIRT6 at residue K33
  - term:
      id: GO:2000781
      label: positive regulation of double-strand break repair
    evidence_type: IDA
    original_reference_id: PMID:32538779
    review:
      summary: SIRT1 supports repair signaling by enabling SIRT6 recruitment to
        DNA breaks.
      action: KEEP_AS_NON_CORE
      reason: DNA repair promotion is a downstream effect of SIRT1 activity.
      supported_by:
        - reference_id: PMID:32538779
          supporting_text: Synergy between SIRT1 and SIRT6 helps recognize DNA 
            breaks and potentiates the DNA damage response and repair in humans 
            and mice.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: PMID:20027304
    review:
      summary: SIRT1 localizes to cytoplasmic compartments.
      action: ACCEPT
      reason: Direct immunostaining shows cytoplasmic localization.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:30193097
    review:
      summary: SIRT1 deacetylates PCK1, supporting NAD-dependent protein lysine
        deacetylase activity.
      action: ACCEPT
      reason: The abstract directly states SIRT1 deacetylates a protein
        substrate (PCK1).
      supported_by:
        - reference_id: PMID:30193097
          supporting_text: SIRT1 deacetylates PCK1
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:15692560
    review:
      summary: SIRT1 deacetylates FOXO1 as an NAD-dependent protein lysine
        deacetylase.
      action: ACCEPT
      reason: Direct deacetylation of a protein substrate is reported.
      supported_by:
        - reference_id: PMID:15692560
          supporting_text: SIRT1, a mammalian homolog of yeast Sir2, bound to
            and deacetylated FOXO1 and inhibited its transcriptional activity.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:23142079
    review:
      summary: SIRT1 is noted as a deacetylase controlling PGC-1α acetylation.
      action: ACCEPT
      reason: The abstract describes SIRT1 as the deacetylase that controls
        PGC-1α acetylation state.
      supported_by:
        - reference_id: PMID:23142079
          supporting_text: PGC-1α's activation of gluconeogenic gene expression
            is dependent upon its acetylation state, which is controlled by
            the acetyltransferase GCN5 and the deacetylase Sirt1.
  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IDA
    original_reference_id: PMID:15692560
    review:
      summary: SIRT1 influences gluconeogenic gene expression via FOXO1.
      action: KEEP_AS_NON_CORE
      reason: Gluconeogenesis regulation is a downstream metabolic effect.
      supported_by:
        - reference_id: PMID:15692560
          supporting_text: SIRT1, a mammalian homolog of yeast Sir2, bound to
            and deacetylated FOXO1 and inhibited its transcriptional activity.
  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IDA
    original_reference_id: PMID:23142079
    review:
      summary: SIRT1 regulates gluconeogenic gene expression via PGC-1α
        acetylation control.
      action: KEEP_AS_NON_CORE
      reason: Gluconeogenesis regulation is a downstream metabolic effect.
      supported_by:
        - reference_id: PMID:23142079
          supporting_text: PGC-1α's activation of gluconeogenic gene expression
            is dependent upon its acetylation state, which is controlled by
            the acetyltransferase GCN5 and the deacetylase Sirt1.
  - term:
      id: GO:0051658
      label: maintenance of nucleus location
    evidence_type: IDA
    original_reference_id: PMID:15692560
    review:
      summary: Maintenance of nucleus location is not described in this study.
      action: REMOVE
      reason: No evidence for nuclear positioning in the FOXO1 deacetylation
        study.
      supported_by:
        - reference_id: PMID:15692560
          supporting_text: SIRT1, a mammalian homolog of yeast Sir2, bound to
            and deacetylated FOXO1 and inhibited its transcriptional activity.
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:28497810
    review:
      summary: SIRT1 is an NAD-dependent histone deacetylase.
      action: ACCEPT
      reason: Histone deacetylase activity is supported by multiple SIRT1
        studies.
      supported_by:
        - reference_id: PMID:28497810
          supporting_text: class I histone deacetylases (HDACs) rather than
            sirtuin family deacetylases (SIRTs) are the major histone
            decrotonylases
        - reference_id: PMID:15469825
          supporting_text: "SirT1 deacetylates histone polypeptides with a preference
            for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro."
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:29765047
    review:
      summary: SIRT1 is described as a deacetylase in this study, supporting
        NAD-dependent protein lysine deacetylase activity.
      action: ACCEPT
      reason: The abstract explicitly identifies Sirt1 as the deacetylase
        repressing TAG synthesis.
      supported_by:
        - reference_id: PMID:29765047
          supporting_text: repressed by deacetylase Sirt1.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:30409912
    review:
      summary: SIRT1 reverses TIP60-mediated HEC1 acetylation, supporting
        NAD-dependent protein lysine deacetylase activity.
      action: ACCEPT
      reason: The abstract notes SIRT1 specifically reverses HEC1 acetylation.
      supported_by:
        - reference_id: PMID:30409912
          supporting_text: TIP60-mediated acetylation was specifically reversed by sirtuin 1 (SIRT1).
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:32034146
    review:
      summary: NAD-dependent protein lysine deacetylase activity is the core
        enzymatic function of SIRT1.
      action: ACCEPT
      reason: Core molecular function supported by multiple experimental
        studies.
      supported_by:
        - reference_id: PMID:32034146
          supporting_text: TIP60, also known as KAT5, a haplo-insufficient tumor suppressor, directly acetylates XPF
        - reference_id: PMID:15692560
          supporting_text: SIRT1, a mammalian homolog of yeast Sir2, bound to
            and deacetylated FOXO1 and inhibited its transcriptional activity.
  - term:
      id: GO:0160012
      label: histone decrotonylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:28497810
    review:
      summary: This study indicates sirtuins are not the major histone
        decrotonylases.
      action: REMOVE
      reason: Evidence points to class I HDACs, not SIRT1, as major
        decrotonylases.
      supported_by:
        - reference_id: PMID:28497810
          supporting_text: class I histone deacetylases (HDACs) rather than
            sirtuin family deacetylases (SIRTs) are the major histone
            decrotonylases
  - term:
      id: GO:0010868
      label: negative regulation of triglyceride biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:29765047
    review:
      summary: SIRT1 represses TAG synthesis in this system.
      action: KEEP_AS_NON_CORE
      reason: The study reports repression of TAG synthesis by SIRT1, a
        metabolic regulation role rather than a core function.
      supported_by:
        - reference_id: PMID:29765047
          supporting_text: synthesis, which is repressed by deacetylase Sirt1.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:20100829
    review:
      summary: SIRT1 deacetylates TIP60 as an NAD-dependent protein lysine
        deacetylase.
      action: ACCEPT
      reason: Direct deacetylation of TIP60 is reported.
      supported_by:
        - reference_id: PMID:20100829
          supporting_text: we identified SIRT1 that specifically deacetylates
            TIP60 and negatively regulates TIP60 activity in vivo.
  - term:
      id: GO:0140861
      label: DNA repair-dependent chromatin remodeling
    evidence_type: IDA
    original_reference_id: PMID:20100829
    review:
      summary: DNA repair-dependent chromatin remodeling is not directly
        demonstrated here.
      action: UNDECIDED
      reason: The abstract focuses on TIP60 autoacetylation and SIRT1
        deacetylation, not chromatin remodeling.
      supported_by:
        - reference_id: PMID:20100829
          supporting_text: TIP60 is autoacetylated in response to UV damage
  - term:
      id: GO:0140297
      label: DNA-binding transcription factor binding
    evidence_type: IPI
    original_reference_id: PMID:20955178
    review:
      summary: SIRT1 binds the transcription factor XBP1s for deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Represents a context-specific transcription factor interaction.
      supported_by:
        - reference_id: PMID:20955178
          supporting_text: In the present study, we demonstrate that XBP1s is
            a target of acetylation and deacetylation mediated by p300 and
            SIRT1 (sirtuin 1) respectively
  - term:
      id: GO:0140297
      label: DNA-binding transcription factor binding
    evidence_type: IPI
    original_reference_id: PMID:23382074
    review:
      summary: SIRT1 interacts with transcription factors in specific contexts.
      action: KEEP_AS_NON_CORE
      reason: Represents a context-specific transcription factor interaction.
      supported_by:
        - reference_id: PMID:23382074
          supporting_text: Feb 4. A high-confidence interaction map identifies 
            SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator
            complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31722219
    review:
      summary: Generic protein binding from this study is not informative for
        SIRT1 function.
      action: REMOVE
      reason: Specific interactions and enzymatic activity are more
        informative than a generic binding term.
      supported_by:
        - reference_id: PMID:31722219
          supporting_text: the acetylation state of CCDC84 at lysine 31 is
            regulated by the deacetylase SIRT1
  - term:
      id: GO:0006476
      label: protein deacetylation
    evidence_type: IDA
    original_reference_id: PMID:31722219
    review:
      summary: SIRT1 deacetylates CCDC84 as a protein deacetylase.
      action: ACCEPT
      reason: Direct evidence that SIRT1 regulates acetylation state of a
        substrate.
      supported_by:
        - reference_id: PMID:31722219
          supporting_text: the acetylation state of CCDC84 at lysine 31 is
            regulated by the deacetylase SIRT1
  - term:
      id: GO:0010824
      label: regulation of centrosome duplication
    evidence_type: IDA
    original_reference_id: PMID:31722219
    review:
      summary: CCDC84 acetylation state affects centrosome duplication, with
        SIRT1 as the deacetylase.
      action: KEEP_AS_NON_CORE
      reason: Centrosome duplication effects are downstream of SIRT1
        deacetylation activity.
      supported_by:
        - reference_id: PMID:31722219
          supporting_text: CCDC84 Acetylation Oscillation Regulates Centrosome
            Duplication by Modulating HsSAS-6 Degradation
  - term:
      id: GO:0106230
      label: protein depropionylation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Evidence for SIRT1 depropionylation activity is not specified in
        this reference.
      action: UNDECIDED
      reason: GO_REF:0000024 does not provide direct experimental support here.
  - term:
      id: GO:0106231
      label: NAD-dependent protein-lysine depropionylase activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 exhibits NAD-dependent deacylase activities including
        depropionylation in some contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream enzymatic activity beyond core deacetylation.
  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IDA
    original_reference_id: PMID:30193097
    review:
      summary: SIRT1 promotes gluconeogenic activity via PCK1 deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Gluconeogenesis regulation is a downstream metabolic effect.
      supported_by:
        - reference_id: PMID:30193097
          supporting_text: Dynamic Acetylation of Phosphoenolpyruvate 
            Carboxykinase Toggles Enzyme Activity between Gluconeogenic and 
            Anaplerotic Reactions.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29656858
    review:
      summary: This paper is about PACS2 variants and does not provide SIRT1
        binding evidence.
      action: REMOVE
      reason: No SIRT1 interactions are described.
      supported_by:
        - reference_id: PMID:29656858
          supporting_text: A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.
  - term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:23960241
    review:
      summary: This study links TGF-β signaling to Sirt1 silencing, but does
        not place SIRT1 within the receptor signaling pathway.
      action: REMOVE
      reason: SIRT1 is a downstream target rather than a component of TGF-β
        receptor signaling.
      supported_by:
        - reference_id: PMID:23960241
          supporting_text: MeCP2 inhibited endothelial angiogenic
            characteristics partly by epigenetic silencing of Sirt1.
  - term:
      id: GO:0043536
      label: positive regulation of blood vessel endothelial cell migration
    evidence_type: IDA
    original_reference_id: PMID:23960241
    review:
      summary: Sirt1 influences endothelial angiogenic functions affected by
        TGF-β/MeCP2.
      action: KEEP_AS_NON_CORE
      reason: Context-specific effect on endothelial migration/angiogenic
        function.
      supported_by:
        - reference_id: PMID:23960241
          supporting_text: involvement of MeCP2/Sirt1 in the regulation of
            angiogenic functions of endothelial cells.
  - term:
      id: GO:0045766
      label: positive regulation of angiogenesis
    evidence_type: IDA
    original_reference_id: PMID:23960241
    review:
      summary: Sirt1 contributes to angiogenic functions in endothelial cells.
      action: KEEP_AS_NON_CORE
      reason: Represents downstream functional impact rather than core
        enzymatic role.
      supported_by:
        - reference_id: PMID:23960241
          supporting_text: involvement of MeCP2/Sirt1 in the regulation of
            angiogenic functions of endothelial cells.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IMP
    original_reference_id: PMID:20424141
    review:
      summary: Sirt1 modulation affects acetylation status of FOXO1,
        consistent with protein lysine deacetylase activity.
      action: ACCEPT
      reason: Changes in Sirt1 levels alter acetylated FOXO1.
      supported_by:
        - reference_id: PMID:20424141
          supporting_text: overexpression of miR-34a increased the level of
            Sirt1 effector-acetylated forkhead box O transcription factors 1
            (FoxO1)
  - term:
      id: GO:0045766
      label: positive regulation of angiogenesis
    evidence_type: IMP
    original_reference_id: PMID:20424141
    review:
      summary: Sirt1 suppression impairs EPC-mediated angiogenesis.
      action: KEEP_AS_NON_CORE
      reason: Angiogenesis phenotype is downstream of Sirt1 regulation.
      supported_by:
        - reference_id: PMID:20424141
          supporting_text: miR-34a inhibits EPC-mediated angiogenesis by
            inducing senescence via suppressing Sirt1.
  - term:
      id: GO:2000773
      label: negative regulation of cellular senescence
    evidence_type: IMP
    original_reference_id: PMID:20424141
    review:
      summary: Sirt1 suppression induces senescence in EPCs.
      action: KEEP_AS_NON_CORE
      reason: Senescence regulation is context-specific.
      supported_by:
        - reference_id: PMID:20424141
          supporting_text: miR-34a inhibits EPC-mediated angiogenesis by
            inducing senescence via suppressing Sirt1.
  - term:
      id: GO:0045766
      label: positive regulation of angiogenesis
    evidence_type: IDA
    original_reference_id: PMID:25217442
    review:
      summary: The study links miR-212/132 effects to suppression of SIRT1 and
        impaired endothelial function, but does not directly show SIRT1 driving
        angiogenesis.
      action: KEEP_AS_NON_CORE
      reason: Evidence is indirect but supports a context-specific role in
        angiogenic regulation.
      supported_by:
        - reference_id: PMID:25217442
          supporting_text: suppression of important endothelial genes such as GAB1 and SIRT1
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12837246
    review:
      summary: SIRT1 influences transcriptional regulation in specific
        contexts.
      action: KEEP_AS_NON_CORE
      reason: Context-specific transcriptional modulation rather than a core
        function.
      supported_by:
        - reference_id: PMID:12837246
          supporting_text: Multiple tumor suppressor pathways negatively regulate telomerase.
  - term:
      id: GO:0042981
      label: regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:19934257
    review:
      summary: SIRT1 influences apoptosis during genotoxic stress via APE1
        regulation.
      action: KEEP_AS_NON_CORE
      reason: Apoptosis effects are downstream of DNA repair modulation.
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: sensitizing cells to death induced by genotoxic
            stress
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:20167603
    review:
      summary: SIRT1 localizes to the nucleus.
      action: ACCEPT
      reason: Nuclear localization is well supported in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0010883
      label: regulation of lipid storage
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences regulation of lipid storage.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0030225
      label: macrophage differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates macrophage differentiation in broader immune
        contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream immune regulation rather than a core function.
  - term:
      id: GO:0060907
      label: positive regulation of macrophage cytokine production
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates macrophage cytokine production.
      action: KEEP_AS_NON_CORE
      reason: Downstream immune regulation rather than a core function.
  - term:
      id: GO:1904179
      label: positive regulation of adipose tissue development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences adipose tissue development.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0045766
      label: positive regulation of angiogenesis
    evidence_type: IMP
    original_reference_id: PMID:24048733
    review:
      summary: SIRT1 induction is reported as part of MCPIP-driven angiogenic
        signaling.
      action: KEEP_AS_NON_CORE
      reason: This reflects a context-specific angiogenic pathway rather than a
        core SIRT1 function.
      supported_by:
        - reference_id: PMID:24048733
          supporting_text: MCPIP-induced angiogenesis is mediated via hypoxia-inducible factor 
            (HIF-1α), vascular endothelial growth factor (VEGF), and silent information 
            regulator (SIRT-1) induction
  - term:
      id: GO:0051897
      label: positive regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 positively modulates PI3K/AKT signaling in some contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling modulation rather than a core function.
  - term:
      id: GO:0090335
      label: regulation of brown fat cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences brown fat cell differentiation.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0033210
      label: leptin-mediated signaling pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences leptin-mediated signaling.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic signaling role rather than a core function.
  - term:
      id: GO:0044321
      label: response to leptin
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 participates in leptin response contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic signaling role rather than a core function.
  - term:
      id: GO:0001938
      label: positive regulation of endothelial cell proliferation
    evidence_type: IMP
    original_reference_id: PMID:20203304
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:20203304
          supporting_text: 2010 Mar 4. SIRT1 promotes proliferation and prevents
            senescence through targeting LKB1 in primary porcine aortic 
            endothelial cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21030595
    review:
      summary: Generic protein binding annotation is uninformative.
      action: REMOVE
      reason: Generic protein binding annotation is uninformative. More specific
        annotations capture the biologically relevant interactions.
      supported_by:
        - reference_id: PMID:21030595
          supporting_text: 2010 Oct 28. HDAC3 is negatively regulated by the 
            nuclear protein DBC1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25661920
    review:
      summary: The study focuses on CCAR2 competition with SIRT1; generic
        protein binding is uninformative.
      action: REMOVE
      reason: A specific SIRT1 interaction context is described, making the
        generic binding term unhelpful.
      supported_by:
        - reference_id: PMID:25661920
          supporting_text: CCAR2 negatively regulates nuclear receptor LXRα by competing with SIRT1 deacetylase.
  - term:
      id: GO:0006476
      label: protein deacetylation
    evidence_type: IMP
    original_reference_id: PMID:24824780
    review:
      summary: SIRT1 inhibition reverses MCC-induced deacetylation of β-catenin.
      action: ACCEPT
      reason: Direct deacetylation effect is supported in this context.
      supported_by:
        - reference_id: PMID:24824780
          supporting_text: Treatment of cells with the SIRT1 inhibitor Nicotinamide reverses MCC-induced deacetylation of β-cat K49.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:20074560
    review:
      summary: DBC1 modulation implicates SIRT1 in transcriptional repression
        contexts.
      action: KEEP_AS_NON_CORE
      reason: Represents context-specific transcriptional repression rather
        than a core function.
      supported_by:
        - reference_id: PMID:20074560
          supporting_text: depletion of the endogenous DBC1 negatively regulates 
            p53-dependent apoptosis through its specific inhibition of SIRT1.
  - term:
      id: GO:0016922
      label: nuclear receptor binding
    evidence_type: IPI
    original_reference_id: PMID:24043310
    review:
      summary: This paper is about SIRT4 and PPARα, not SIRT1.
      action: REMOVE
      reason: No SIRT1 nuclear receptor binding evidence is provided.
      supported_by:
        - reference_id: PMID:24043310
          supporting_text: SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:20955178
    review:
      summary: SIRT1 inhibits XBP1s-dependent transcription.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect of deacetylating a specific transcription
        factor.
      supported_by:
        - reference_id: PMID:20955178
          supporting_text: SIRT1 deacetylates XBP1s and inhibits its
            transcriptional activity
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:20955178
    review:
      summary: SIRT1 is nuclear in studies of XBP1s regulation.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0032922
      label: circadian regulation of gene expression
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates circadian clock components through deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Circadian regulation is a downstream outcome of SIRT1 activity.
  - term:
      id: GO:0006476
      label: protein deacetylation
    evidence_type: IDA
    original_reference_id: PMID:18662546
    review:
      summary: SIRT1 promotes PER2 deacetylation, supporting protein
        deacetylation activity.
      action: ACCEPT
      reason: The abstract reports SIRT1 deacetylation of PER2.
      supported_by:
        - reference_id: PMID:18662546
          supporting_text: SIRT1 regulates circadian clock gene expression through PER2 deacetylation.
  - term:
      id: GO:0032922
      label: circadian regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:18662546
    review:
      summary: SIRT1 regulates circadian clock gene expression through PER2 
        deacetylation (PMID:18662546). While the experimental evidence supports 
        clock regulation, SIRT1 has broad substrate specificity and clock 
        proteins are just one of many targets.
      action: KEEP_AS_NON_CORE
      reason: The IMP evidence from PMID:18662546 specifically demonstrates 
        SIRT1 involvement in circadian regulation. However, this is one of many 
        downstream effects of SIRT1 deacetylase activity on diverse substrates. 
        Not a core function.
      supported_by:
        - reference_id: PMID:18662546
          supporting_text: "SIRT1, an NAD(+)-dependent protein deacetylase, is required
            for high-magnitude circadian transcription of several core clock genes,
            including Bmal1, Rorgamma, Per2, and Cry1."
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23382074
    review:
      summary: Generic protein binding is uninformative relative to specific
        interaction terms.
      action: REMOVE
      reason: Specific enzyme-binding interaction is more informative.
      supported_by:
        - reference_id: PMID:23382074
          supporting_text: as a SIRT1-interacting partner
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:23382074
    review:
      summary: SIRT1 interacts with the deubiquitinating enzyme USP22.
      action: ACCEPT
      reason: Direct interaction with an enzyme partner is reported.
      supported_by:
        - reference_id: PMID:23382074
          supporting_text: as a SIRT1-interacting partner
  - term:
      id: GO:1990254
      label: keratin filament binding
    evidence_type: IPI
    original_reference_id: PMID:23382074
    review:
      summary: Keratin filament binding is not described in this study.
      action: REMOVE
      reason: No evidence for keratin filament binding.
      supported_by:
        - reference_id: PMID:23382074
          supporting_text: as a SIRT1-interacting partner
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IDA
    original_reference_id: PMID:22956909
    review:
      summary: SIRT1 binds chromatin at H1.5 target loci in differentiated
        cells.
      action: ACCEPT
      reason: SIRT1 binding is required for chromatin compaction at H1.5
        targets.
      supported_by:
        - reference_id: PMID:22956909
          supporting_text: H1.5 binding is associated with gene repression and
            is required for SIRT1 binding, H3K9me2 enrichment, and chromatin
            compaction.
  - term:
      id: GO:0006325
      label: chromatin organization
    evidence_type: IMP
    original_reference_id: PMID:22956909
    review:
      summary: SIRT1 contributes to chromatin compaction at H1.5 target loci.
      action: KEEP_AS_NON_CORE
      reason: Represents context-specific chromatin organization effects.
      supported_by:
        - reference_id: PMID:22956909
          supporting_text: H1.5 binding is associated with gene repression and
            is required for SIRT1 binding, H3K9me2 enrichment, and chromatin
            compaction.
  - term:
      id: GO:0042393
      label: histone binding
    evidence_type: IPI
    original_reference_id: PMID:22956909
    review:
      summary: SIRT1 associates with histone H1.5-containing chromatin.
      action: ACCEPT
      reason: Histone association supports histone binding.
      supported_by:
        - reference_id: PMID:22956909
          supporting_text: H1.5 binding is associated with gene repression and
            is required for SIRT1 binding, H3K9me2 enrichment, and chromatin
            compaction.
  - term:
      id: GO:0010629
      label: negative regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:17916362
    review:
      summary: Gene expression changes are specific (PAI-1 and eNOS), not a
        broad repression program.
      action: MARK_AS_OVER_ANNOTATED
      reason: The term is too general for the evidence provided.
      supported_by:
        - reference_id: PMID:17916362
          supporting_text: increased PAI-1 expression and decreased both
            protein expression and activity of eNOS.
  - term:
      id: GO:0090400
      label: stress-induced premature senescence
    evidence_type: IMP
    original_reference_id: PMID:17916362
    review:
      summary: Sirt1 inhibition induces premature senescence-like phenotype in
        endothelial cells.
      action: KEEP_AS_NON_CORE
      reason: Senescence effects are downstream of Sirt1 activity.
      supported_by:
        - reference_id: PMID:17916362
          supporting_text: Sirt1 inhibition increased p53 acetylation and induced
            premature senescence-like phenotype
  - term:
      id: GO:1901984
      label: negative regulation of protein acetylation
    evidence_type: IMP
    original_reference_id: PMID:17916362
    review:
      summary: Sirt1 normally counteracts protein acetylation, as inhibition
        increases p53 acetylation.
      action: ACCEPT
      reason: Direct evidence of increased acetylation upon Sirt1 inhibition.
      supported_by:
        - reference_id: PMID:17916362
          supporting_text: Treatment with sirtinol or Sirt1 siRNA increased
            acetylation of p53
  - term:
      id: GO:0042542
      label: response to hydrogen peroxide
    evidence_type: IDA
    original_reference_id: PMID:19934257
    review:
      summary: Genotoxic stress including H2O2 affects APE1 acetylation
        regulated by SIRT1.
      action: KEEP_AS_NON_CORE
      reason: Represents stress-context regulation rather than a core
        function.
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: H2O2 led to an increase in acetylation of APE1
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3371467
    review:
      summary: SIRT1 is nuclear in contexts including HSF1 regulation.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3371518
    review:
      summary: SIRT1 is nuclear in HSF1 regulatory contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3371537
    review:
      summary: SIRT1 is nuclear in DBC1 regulatory contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-427514
    review:
      summary: SIRT1 is nuclear in eNoSC chromatin regulation contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-427527
    review:
      summary: SIRT1 is nuclear in eNoSC chromatin regulation contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-427528
    review:
      summary: SIRT1 is nuclear in eNoSC complex contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9620532
    review:
      summary: SIRT1 is nuclear in FOXO3 regulation contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9765850
    review:
      summary: SIRT1 is nuclear in transcriptional regulation contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9825772
    review:
      summary: SIRT1 is nuclear in HINT1-related regulatory contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9854916
    review:
      summary: SIRT1 is nuclear in transcriptional regulation contexts.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:1902166
      label: negative regulation of intrinsic apoptotic signaling pathway in 
        response to DNA damage by p53 class mediator
    evidence_type: ISS
    original_reference_id: PMID:11672522
    review:
      summary: Sir2alpha represses p53-dependent apoptosis under DNA damage
        stress.
      action: KEEP_AS_NON_CORE
      reason: The effect is context-specific p53-dependent apoptosis modulation
        rather than a core SIRT1 function.
      supported_by:
        - reference_id: PMID:11672522
          supporting_text: Sir2alpha represses p53-dependent apoptosis in response to DNA damage and 
            oxidative stress
  - term:
      id: GO:1902176
      label: negative regulation of oxidative stress-induced intrinsic apoptotic
        signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:17317627
    review:
      summary: This paper focuses on HuR regulation of SIRT1 expression under
        oxidative stress, not direct apoptosis pathway regulation.
      action: REMOVE
      reason: No direct evidence for negative regulation of oxidative
        stress-induced intrinsic apoptosis by SIRT1 is provided.
      supported_by:
        - reference_id: PMID:17317627
          supporting_text: SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival.
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:23056314
    review:
      summary: Protein lysine deacetylase activity is a core function of SIRT1.
      action: ACCEPT
      reason: Core molecular function supported by multiple SIRT1 studies.
      supported_by:
        - reference_id: PMID:23056314
          supporting_text: VASH1 augmented the synthesis of sirtuin 1 (SIRT1)
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IMP
    original_reference_id: PMID:20670893
    review:
      summary: SIRT1 deacetylates XPA, supporting protein lysine deacetylase
        activity.
      action: ACCEPT
      reason: The study reports direct deacetylation of XPA by SIRT1.
      supported_by:
        - reference_id: PMID:20670893
          supporting_text: SIRT1 deacetylates XPA
  - term:
      id: GO:0070914
      label: UV-damage excision repair
    evidence_type: IMP
    original_reference_id: PMID:20670893
    review:
      summary: SIRT1 regulates the NER pathway in UV-damage excision repair
        contexts.
      action: KEEP_AS_NON_CORE
      reason: SIRT1 modulates NER via XPA deacetylation, but this is a specific
        downstream process rather than a core function.
      supported_by:
        - reference_id: PMID:20670893
          supporting_text: SIRT1 regulates NER pathway
  - term:
      id: GO:0035358
      label: regulation of peroxisome proliferator activated receptor signaling 
        pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates PPAR signaling in metabolic contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0010875
      label: positive regulation of cholesterol efflux
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences cholesterol efflux.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0031648
      label: protein destabilization
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 can influence protein stability in specific contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream regulatory effect rather than a core function.
  - term:
      id: GO:0035356
      label: intracellular triglyceride homeostasis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 contributes to intracellular triglyceride homeostasis.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0042632
      label: cholesterol homeostasis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 contributes to cholesterol homeostasis.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0031393
      label: negative regulation of prostaglandin biosynthetic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates prostaglandin biosynthesis in specific contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream regulatory effect rather than a core function.
  - term:
      id: GO:0070857
      label: regulation of bile acid biosynthetic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences bile acid biosynthesis regulation.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:2000111
      label: positive regulation of macrophage apoptotic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates macrophage apoptotic processes.
      action: KEEP_AS_NON_CORE
      reason: Downstream immune regulation rather than a core function.
  - term:
      id: GO:0030512
      label: negative regulation of transforming growth factor beta receptor 
        signaling pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates TGF-beta signaling in specific contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling regulation rather than a core function.
  - term:
      id: GO:0034391
      label: regulation of smooth muscle cell apoptotic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences smooth muscle cell apoptotic processes.
      action: KEEP_AS_NON_CORE
      reason: Downstream cell-type-specific regulation rather than a core function.
  - term:
      id: GO:2000481
      label: positive regulation of cAMP-dependent protein kinase activity
    evidence_type: IMP
    original_reference_id: PMID:18687677
    review:
      summary: The study addresses LKB1/AMPK activation, not cAMP-dependent
        protein kinase activity.
      action: REMOVE
      reason: The abstract discusses AMP-activated protein kinase signaling
        rather than cAMP-dependent protein kinase regulation.
      supported_by:
        - reference_id: PMID:18687677
          supporting_text: AMP-activated protein kinase (AMPK)
  - term:
      id: GO:2000773
      label: negative regulation of cellular senescence
    evidence_type: IDA
    original_reference_id: PMID:20203304
    review:
      summary: Increasing SIRT1 levels blocks LKB1-induced cellular
        senescence.
      action: KEEP_AS_NON_CORE
      reason: Senescence regulation is context-specific downstream biology.
      supported_by:
        - reference_id: PMID:20203304
          supporting_text: Overexpression of LKB1 promoted cellular senescence
            and retarded endothelial proliferation, which could be blocked by
            increasing SIRT1 levels.
  - term:
      id: GO:2000774
      label: positive regulation of cellular senescence
    evidence_type: IDA
    original_reference_id: PMID:18687677
    review:
      summary: This paper focuses on LKB1 deacetylation and AMPK activation,
        not cellular senescence.
      action: REMOVE
      reason: There is no reported senescence phenotype in the abstract; the
        evidence centers on AMPK signaling.
      supported_by:
        - reference_id: PMID:18687677
          supporting_text: AMP-activated protein kinase (AMPK)
  - term:
      id: GO:0032007
      label: negative regulation of TOR signaling
    evidence_type: IMP
    original_reference_id: PMID:20169165
    review:
      summary: SIRT1 negatively regulates mTOR signaling via TSC2.
      action: KEEP_AS_NON_CORE
      reason: mTOR pathway regulation is a downstream signaling role rather
        than a core enzymatic function.
      supported_by:
        - reference_id: PMID:20169165
          supporting_text: SIRT1 negatively regulates the mammalian target of rapamycin.
  - term:
      id: GO:0043124
      label: negative regulation of canonical NF-kappaB signal transduction
    evidence_type: IDA
    original_reference_id: PMID:17680780
    review:
      summary: Sirt1 and TLE1 repress NF-kappaB activity.
      action: KEEP_AS_NON_CORE
      reason: NF-kappaB repression is a specific downstream regulatory effect
        of SIRT1.
      supported_by:
        - reference_id: PMID:17680780
          supporting_text: Sirt1 and TLE1 repress NF-kappaB activity.
  - term:
      id: GO:0001934
      label: positive regulation of protein phosphorylation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: No direct evidence for SIRT1 in positive regulation of protein
        phosphorylation is provided here.
      action: UNDECIDED
      reason: GO_REF:0000024 does not provide direct experimental support.
  - term:
      id: GO:0032868
      label: response to insulin
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates insulin response through deacetylation of
        insulin signaling regulators.
      action: KEEP_AS_NON_CORE
      reason: Downstream signaling modulation rather than a core function.
  - term:
      id: GO:0046628
      label: positive regulation of insulin receptor signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:21241768
    review:
      summary: SIRT1 positively modulates insulin signaling via PI3K in muscle
        cells.
      action: KEEP_AS_NON_CORE
      reason: This is a context-specific signaling modulation downstream of
        SIRT1 activity.
      supported_by:
        - reference_id: PMID:21241768
          supporting_text: SIRT1 as a positive modulator of insulin signaling in muscle cells through PI3K
  - term:
      id: GO:0002821
      label: positive regulation of adaptive immune response
    evidence_type: IDA
    original_reference_id: PMID:21890893
    review:
      summary: The evidence supports SIRT1-enhanced MHC II transcription, a
        specific step within adaptive immunity.
      action: MARK_AS_OVER_ANNOTATED
      reason: The study demonstrates MHC II transactivation rather than broad
        positive regulation of the adaptive immune response.
      supported_by:
        - reference_id: PMID:21890893
          supporting_text: SIRT1 activation augments MHC II transcription
  - term:
      id: GO:0045348
      label: positive regulation of MHC class II biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:21890893
    review:
      summary: SIRT1 activation augments MHC II transcription via CIITA.
      action: KEEP_AS_NON_CORE
      reason: This reflects immune regulation downstream of SIRT1 activity
        rather than a core enzymatic function.
      supported_by:
        - reference_id: PMID:21890893
          supporting_text: SIRT1 activation augments MHC II transcription
  - term:
      id: GO:0035098
      label: ESC/E(Z) complex
    evidence_type: IDA
    original_reference_id: PMID:15684044
    review:
      summary: SirT1 is reported as a component of a PRC4 polycomb complex.
      action: KEEP_AS_NON_CORE
      reason: The study describes SIRT1 in a polycomb complex context, which is
        not a core function.
      supported_by:
        - reference_id: PMID:15684044
          supporting_text: PRC4, that contains the NAD+-dependent histone deacetylase SirT1
  - term:
      id: GO:0000012
      label: single strand break repair
    evidence_type: IMP
    original_reference_id: PMID:20097625
    review:
      summary: This study demonstrates SIRT1 promotion of homologous
        recombination, not single-strand break repair.
      action: REMOVE
      reason: The evidence is specific to double-strand break repair via HR.
      supported_by:
        - reference_id: PMID:20097625
          supporting_text: SIRT1 activity promotes homologous recombination (HR) in human cells.
  - term:
      id: GO:0001678
      label: intracellular glucose homeostasis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 participates in glucose homeostasis regulation.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0010906
      label: regulation of glucose metabolic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 modulates glucose metabolic processes.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0055089
      label: fatty acid homeostasis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences fatty acid homeostasis.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0016239
      label: positive regulation of macroautophagy
    evidence_type: IDA
    original_reference_id: PMID:18296641
    review:
      summary: Increased Sirt1 expression stimulates autophagy and Sirt1
        deficiency impairs autophagy activation.
      action: KEEP_AS_NON_CORE
      reason: Autophagy regulation is a downstream process rather than the core
        deacetylase activity.
      supported_by:
        - reference_id: PMID:18296641
          supporting_text: transient increased expression of Sirt1 is sufficient to stimulate basal rates of autophagy.
  - term:
      id: GO:0000720
      label: pyrimidine dimer repair by nucleotide-excision repair
    evidence_type: IMP
    original_reference_id: PMID:21149730
    review:
      summary: SIRT1 regulates global genome nucleotide excision repair via XPC.
      action: KEEP_AS_NON_CORE
      reason: The paper supports NER involvement but this is a specific
        downstream DNA repair role.
      supported_by:
        - reference_id: PMID:21149730
          supporting_text: SIRT1 impairs global genome NER
  - term:
      id: GO:0000731
      label: DNA synthesis involved in DNA repair
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 participates in DNA repair-related synthesis contexts.
      action: KEEP_AS_NON_CORE
      reason: Downstream DNA repair role rather than a core function.
  - term:
      id: GO:0042326
      label: negative regulation of phosphorylation
    evidence_type: IMP
    original_reference_id: PMID:17612497
    review:
      summary: The study indicates SIRT1 is required for NBS1 phosphorylation,
        not negative regulation of phosphorylation.
      action: REMOVE
      reason: Evidence shows SIRT1 supports phosphorylation rather than
        suppressing it.
      supported_by:
        - reference_id: PMID:17612497
          supporting_text: required for ionizing radiation-induced NBS1 Ser343 phosphorylation.
  - term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase
        B signal transduction
    evidence_type: IMP
    original_reference_id: PMID:21149730
    review:
      summary: SIRT1 modulates an AKT-dependent localization step but direct
        negative regulation of PI3K/AKT signaling is not shown.
      action: KEEP_AS_NON_CORE
      reason: The evidence is indirect but indicates a regulatory role in this
        signaling context.
      supported_by:
        - reference_id: PMID:21149730
          supporting_text: reducing AKT-dependent nuclear localization
  - term:
      id: GO:0071479
      label: cellular response to ionizing radiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 participates in responses to ionizing radiation.
      action: KEEP_AS_NON_CORE
      reason: Downstream stress-response role rather than a core function.
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IDA
    original_reference_id: PMID:15152190
    review:
      summary: SIRT1 activity augments TNFalpha-induced apoptosis.
      action: KEEP_AS_NON_CORE
      reason: The apoptotic effect is stimulus-specific and not a core function.
      supported_by:
        - reference_id: PMID:15152190
          supporting_text: augments apoptosis in response to TNFalpha
  - term:
      id: GO:0071356
      label: cellular response to tumor necrosis factor
    evidence_type: IDA
    original_reference_id: PMID:15152190
    review:
      summary: SIRT1 sensitizes cells to TNFalpha-induced apoptosis.
      action: KEEP_AS_NON_CORE
      reason: This reflects a context-specific TNF response rather than a core
        SIRT1 function.
      supported_by:
        - reference_id: PMID:15152190
          supporting_text: sensitization of cells to TNFalpha-induced apoptosis.
  - term:
      id: GO:0007346
      label: regulation of mitotic cell cycle
    evidence_type: IDA
    original_reference_id: PMID:15692560
    review:
      summary: Mitotic cell cycle regulation is not described in this study.
      action: REMOVE
      reason: No evidence for mitotic cell cycle regulation in this FOXO1
        study.
      supported_by:
        - reference_id: PMID:15692560
          supporting_text: SIRT1, a mammalian homolog of yeast Sir2, bound to
            and deacetylated FOXO1 and inhibited its transcriptional activity.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:16892051
    review:
      summary: SirT1 knockdown increases E2F1 apoptotic functions, indicating
        SirT1 suppresses apoptosis in this context.
      action: KEEP_AS_NON_CORE
      reason: The effect is context-specific regulation of E2F1-mediated
        apoptosis.
      supported_by:
        - reference_id: PMID:16892051
          supporting_text: Knockdown of SirT1 by small interference RNA (siRNA) 
            increases E2F1 transcriptional and apoptotic functions.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:15692560
    review:
      summary: SIRT1 inhibits FOXO1 transcriptional activity via
        deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Downstream effect on a specific transcription factor, not core
        function.
      supported_by:
        - reference_id: PMID:15692560
          supporting_text: SIRT1, a mammalian homolog of yeast Sir2, bound to
            and deacetylated FOXO1 and inhibited its transcriptional activity.
  - term:
      id: GO:0001525
      label: angiogenesis
    evidence_type: IDA
    original_reference_id: PMID:20620956
    review:
      summary: SIRT1 negatively affects angiogenesis in vivo.
      action: KEEP_AS_NON_CORE
      reason: The study reports an effect on angiogenesis downstream of SIRT1
        regulation of HIF-1alpha, which is not a core function.
      supported_by:
        - reference_id: PMID:20620956
          supporting_text: SIRT1 has negative effects on tumor growth and angiogenesis.
  - term:
      id: GO:0006979
      label: response to oxidative stress
    evidence_type: IDA
    original_reference_id: PMID:14976264
    review:
      summary: SIRT1 shifts FOXO3 responses toward resistance to oxidative
        stress.
      action: KEEP_AS_NON_CORE
      reason: This is a downstream stress-response outcome of SIRT1 activity.
      supported_by:
        - reference_id: PMID:14976264
          supporting_text: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress
  - term:
      id: GO:0016567
      label: protein ubiquitination
    evidence_type: IDA
    original_reference_id: PMID:21841822
    review:
      summary: SIRT1 deacetylation of FOXO3 promotes ubiquitination and
        degradation.
      action: KEEP_AS_NON_CORE
      reason: The evidence reflects a specific regulatory mechanism rather than
        a core SIRT1 function.
      supported_by:
        - reference_id: PMID:21841822
          supporting_text: Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination
  - term:
      id: GO:0042771
      label: intrinsic apoptotic signaling pathway in response to DNA damage by 
        p53 class mediator
    evidence_type: IMP
    original_reference_id: PMID:20100829
    review:
      summary: This study links TIP60 to UV damage responses, but intrinsic
        apoptotic signaling is not directly demonstrated.
      action: MARK_AS_OVER_ANNOTATED
      reason: Apoptotic pathway specificity is beyond the presented evidence.
      supported_by:
        - reference_id: PMID:20100829
          supporting_text: TIP60 is autoacetylated in response to UV damage
  - term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    evidence_type: IMP
    original_reference_id: PMID:21841822
    review:
      summary: SIRT1-driven FOXO3 degradation is proteasome dependent.
      action: KEEP_AS_NON_CORE
      reason: The study demonstrates a proteasome-dependent outcome for FOXO3
        turnover downstream of SIRT1.
      supported_by:
        - reference_id: PMID:21841822
          supporting_text: process is proteasome dependent.
  - term:
      id: GO:0071456
      label: cellular response to hypoxia
    evidence_type: IMP
    original_reference_id: PMID:20620956
    review:
      summary: SIRT1 modulates cellular responses to hypoxia via HIF-1alpha
        deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Hypoxia response is a context-specific downstream process of
        SIRT1 activity.
      supported_by:
        - reference_id: PMID:20620956
          supporting_text: Sirtuin 1 modulates cellular responses to hypoxia by 
            deacetylating hypoxia-inducible factor 1alpha.
  - term:
      id: GO:2000757
      label: negative regulation of peptidyl-lysine acetylation
    evidence_type: IDA
    original_reference_id: PMID:20100829
    review:
      summary: SIRT1 deacetylates TIP60, negatively regulating lysine
        acetylation.
      action: ACCEPT
      reason: Direct deacetylation supports negative regulation of lysine
        acetylation.
      supported_by:
        - reference_id: PMID:20100829
          supporting_text: we identified SIRT1 that specifically deacetylates
            TIP60 and negatively regulates TIP60 activity in vivo.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:21947282
    review:
      summary: SIRT1-mediated deacetylation of DNMT1 supports gene silencing.
      action: KEEP_AS_NON_CORE
      reason: The evidence indicates transcriptional silencing via DNMT1
        regulation, a downstream effect rather than a core SIRT1 function.
      supported_by:
        - reference_id: PMID:21947282
          supporting_text: SIRT1-mediated deacetylation of DNMT1 is crucial for DNMT1's 
            multiple effects in gene silencing.
  - term:
      id: GO:0006346
      label: DNA methylation-dependent constitutive heterochromatin formation
    evidence_type: TAS
    original_reference_id: PMID:21947282
    review:
      summary: The study links SIRT1 to DNMT1-mediated gene silencing but does
        not demonstrate constitutive heterochromatin formation.
      action: MARK_AS_OVER_ANNOTATED
      reason: Evidence supports DNMT1 activity and gene silencing, not
        heterochromatin formation specifically.
      supported_by:
        - reference_id: PMID:21947282
          supporting_text: SIRT1-mediated deacetylation of DNMT1 is crucial for DNMT1's 
            multiple effects in gene silencing.
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: IMP
    original_reference_id: PMID:21807113
    review:
      summary: Sirt1 supports proliferation in K562 cells via c-Myc activity.
      action: KEEP_AS_NON_CORE
      reason: Proliferation effects are context-specific downstream outcomes.
      supported_by:
        - reference_id: PMID:21807113
          supporting_text: suppress cell proliferation and arrest cell cycle
            at G1/S phase
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:21807113
    review:
      summary: Sirt1 deacetylates c-Myc in vitro and in vivo.
      action: ACCEPT
      reason: Direct substrate deacetylation is reported.
      supported_by:
        - reference_id: PMID:21807113
          supporting_text: deacetylates c-Myc both in vitro and in vivo
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:19047049
    review:
      summary: SIRT1 activation in this context leads to caspase-3 activation
        and apoptosis.
      action: KEEP_AS_NON_CORE
      reason: Apoptotic effects are context-specific in breast tumor cells.
      supported_by:
        - reference_id: PMID:19047049
          supporting_text: lead to an activation of caspase-3
  - term:
      id: GO:0043425
      label: bHLH transcription factor binding
    evidence_type: IPI
    original_reference_id: PMID:21807113
    review:
      summary: Sirt1 physically interacts with c-Myc, a bHLH transcription
        factor.
      action: ACCEPT
      reason: Direct physical interaction is reported.
      supported_by:
        - reference_id: PMID:21807113
          supporting_text: Sirt1 interacts physically with the C-terminus of
            c-Myc
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:21807113
    review:
      summary: Sirt1 enhances c-Myc/Max transcriptional activity.
      action: KEEP_AS_NON_CORE
      reason: Context-specific transcriptional modulation rather than a core
        function.
      supported_by:
        - reference_id: PMID:21807113
          supporting_text: Sirt1 deacetylates c-Myc and promotes c-Myc/Max 
            association.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21212262
    review:
      summary: Generic protein binding is uninformative relative to specific
        mechanistic interactions.
      action: REMOVE
      reason: The study focuses on MST1 regulation of SIRT1 activity rather
        than a specific binding annotation.
      supported_by:
        - reference_id: PMID:21212262
          supporting_text: Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity.
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:21775285
    review:
      summary: SIRT1 deacetylates Akt and PDK1, supporting NAD-dependent protein
        lysine deacetylase activity.
      action: ACCEPT
      reason: The abstract reports deacetylation by SIRT1 that enables Akt/PDK1
        activation.
      supported_by:
        - reference_id: PMID:21775285
          supporting_text: Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3)
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:21775285
    review:
      summary: Akt/PDK1 activation by SIRT1 can influence cell survival.
      action: KEEP_AS_NON_CORE
      reason: Represents a context-specific survival signaling effect.
      supported_by:
        - reference_id: PMID:21775285
          supporting_text: Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3)
  - term:
      id: GO:2000655
      label: negative regulation of cellular response to testosterone stimulus
    evidence_type: IMP
    original_reference_id: PMID:17505061
    review:
      summary: SIRT1 dampens androgen-response transcription under antagonist
        conditions.
      action: KEEP_AS_NON_CORE
      reason: Specific to androgen receptor signaling context.
      supported_by:
        - reference_id: PMID:17505061
          supporting_text: is required for androgen antagonist-mediated
            transcriptional repression and growth suppression
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IDA
    original_reference_id: PMID:17505061
    review:
      summary: SIRT1 is recruited to chromatin at AR-responsive promoters.
      action: ACCEPT
      reason: Promoter-localized deacetylation supports chromatin association.
      supported_by:
        - reference_id: PMID:17505061
          supporting_text: androgen receptor (AR) recruits SIRT1 and nuclear
            receptor corepressor to AR-responsive promoters and deacetylates
            histone H3 locally
  - term:
      id: GO:0060766
      label: negative regulation of androgen receptor signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:17505061
    review:
      summary: SIRT1 negatively regulates androgen receptor signaling under
        antagonist conditions.
      action: KEEP_AS_NON_CORE
      reason: Specific signaling-context effect rather than core function.
      supported_by:
        - reference_id: PMID:17505061
          supporting_text: is required for androgen antagonist-mediated
            transcriptional repression and growth suppression
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:20027304
    review:
      summary: SIRT1 localizes to the nucleus.
      action: ACCEPT
      reason: Direct immunostaining shows nuclear localization.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:20027304
    review:
      summary: SIRT1 localizes to the cytoplasm.
      action: ACCEPT
      reason: Direct immunostaining shows cytoplasmic localization.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0051019
      label: mitogen-activated protein kinase binding
    evidence_type: IPI
    original_reference_id: PMID:20027304
    review:
      summary: SIRT1 physically interacts with the MAPK JNK1.
      action: ACCEPT
      reason: Coimmunoprecipitation demonstrates JNK1 interaction.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: We identified a functional interaction between cJUN
            N-terminal kinase (JNK1) and SIRT1
  - term:
      id: GO:0070301
      label: cellular response to hydrogen peroxide
    evidence_type: IDA
    original_reference_id: PMID:20027304
    review:
      summary: SIRT1 responds to oxidative stress by changing nuclear
        localization.
      action: KEEP_AS_NON_CORE
      reason: Stress-responsive localization is a context-specific regulatory
        effect.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: Treatment with H2O2 increased nuclear localization
            of SIRT1
  - term:
      id: GO:0018394
      label: peptidyl-lysine acetylation
    evidence_type: IMP
    original_reference_id: PMID:18004385
    review:
      summary: SIRT1 deacetylates SUV39H1; this is deacetylation rather than
        acetylation.
      action: REMOVE
      reason: The evidence supports deacetylation activity, not acetylation.
      supported_by:
        - reference_id: PMID:18004385
          supporting_text: SIRT1 interacts directly with, recruits and deacetylates SUV39H1
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12535671
    review:
      summary: SIRT1 contributes to transcriptional repression mediated by
        HES1/HEY2.
      action: KEEP_AS_NON_CORE
      reason: Context-specific repression via bHLH factors.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: SIRT1-dependent and -independent deacetylase
            pathways are involved in the transcriptional repressions
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: IDA
    original_reference_id: PMID:12535671
    review:
      summary: SIRT1 functions as a transcriptional corepressor with
        HES1/HEY2.
      action: ACCEPT
      reason: Corepressor activity is directly supported.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: SIRT1-dependent and -independent deacetylase
            pathways are involved in the transcriptional repressions
  - term:
      id: GO:0043398
      label: HLH domain binding
    evidence_type: IPI
    original_reference_id: PMID:12535671
    review:
      summary: SIRT1 associates with HLH/bHLH repressors HES1 and HEY2.
      action: ACCEPT
      reason: Physical association with bHLH proteins is reported.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: SIRT1, also physically associates with the human
            bHLH repressor proteins, hHES1 and hHEY2
  - term:
      id: GO:0043425
      label: bHLH transcription factor binding
    evidence_type: IPI
    original_reference_id: PMID:12535671
    review:
      summary: SIRT1 binds bHLH transcription factors HES1 and HEY2.
      action: ACCEPT
      reason: Direct interaction with bHLH factors is reported.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: SIRT1, also physically associates with the human
            bHLH repressor proteins, hHES1 and hHEY2
  - term:
      id: GO:0000791
      label: euchromatin
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: SIRT1 was targeted to a reporter integrated in euchromatin in
        this study.
      action: KEEP_AS_NON_CORE
      reason: Represents context-specific targeting rather than core
        localization.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: a Gal4-reporter integrated in euchromatin
  - term:
      id: GO:0000792
      label: heterochromatin
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: SIRT1 promotes heterochromatin formation via histone
        deacetylation.
      action: ACCEPT
      reason: Core chromatin silencing function in this reference.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1-mediated heterochromatin formation that
            includes deacetylation of histone tails
  - term:
      id: GO:0005637
      label: nuclear inner membrane
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: Nuclear inner membrane localization is supported by broader
        SIRT1 localization evidence.
      action: ACCEPT
      reason: Consistent with curated localization annotations for SIRT1.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0046969
      label: histone H3K9 deacetylase activity, NAD-dependent
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 deacetylates histone H3K9 as part of its core activity.
      action: ACCEPT
      reason: Supported by multiple SIRT1 histone deacetylase studies.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:19934257
    review:
      summary: SIRT1 is nuclear in studies of APE1 regulation.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0032071
      label: regulation of endodeoxyribonuclease activity
    evidence_type: IMP
    original_reference_id: PMID:19934257
    review:
      summary: SIRT1 deacetylates APE1, modulating its endonuclease activity.
      action: ACCEPT
      reason: APE1 is a direct SIRT1 substrate in base excision repair.
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: SIRT1 deacetylates APE1 in vitro and in vivo
            targeting lysines 6 and 7
  - term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:19934257
    review:
      summary: APE1 is a target of the SIRT1 protein deacetylase.
      action: ACCEPT
      reason: Direct substrate deacetylation supports this activity.
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: APE1 is a target of the SIRTUIN1 (SIRT1) protein
            deacetylase
  - term:
      id: GO:0045739
      label: positive regulation of DNA repair
    evidence_type: IMP
    original_reference_id: PMID:19934257
    review:
      summary: SIRT1 promotes base excision repair and genomic integrity.
      action: ACCEPT
      reason: Evidence supports a positive role in DNA repair pathways.
      supported_by:
        - reference_id: PMID:19934257
          supporting_text: SIRT1 plays a vital role in maintaining genomic
            integrity through regulation of the BER pathway
  - term:
      id: GO:0006476
      label: protein deacetylation
    evidence_type: IDA
    original_reference_id: PMID:20027304
    review:
      summary: SIRT1 catalyzes protein deacetylation.
      action: ACCEPT
      reason: Core biochemical process of SIRT1 activity.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 is a NAD-dependent deacetylase that regulates
            a variety of pathways
  - term:
      id: GO:0000183
      label: rDNA heterochromatin formation
    evidence_type: IDA
    original_reference_id: PMID:18485871
    review:
      summary: eNoSC containing SIRT1 establishes silent chromatin at rDNA
        loci.
      action: ACCEPT
      reason: Supported by the eNoSC complex and rDNA chromatin silencing.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: eNoSC contains Nucleomethylin, which binds histone
            H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1
            and SUV39H1.
        - reference_id: PMID:18485871
          supporting_text: thus establishing silent chromatin in the rDNA
            locus.
  - term:
      id: GO:0005677
      label: chromatin silencing complex
    evidence_type: IDA
    original_reference_id: PMID:18485871
    review:
      summary: SIRT1 is part of the eNoSC chromatin silencing complex.
      action: ACCEPT
      reason: Complex membership is explicitly described.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: eNoSC contains Nucleomethylin, which binds histone
            H3 dimethylated Lys9 in the rDNA locus, in a complex with SIRT1
            and SUV39H1.
  - term:
      id: GO:0033553
      label: rDNA heterochromatin
    evidence_type: IDA
    original_reference_id: PMID:18485871
    review:
      summary: Silent chromatin is established at rDNA loci by eNoSC.
      action: ACCEPT
      reason: Supports rDNA heterochromatin at the locus.
      supported_by:
        - reference_id: PMID:18485871
          supporting_text: thus establishing silent chromatin in the rDNA
            locus.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: PMID:16079181
    review:
      summary: SIRT1 is among the nuclear sirtuins with distinct subnuclear
        localizations.
      action: ACCEPT
      reason: The study identifies SIRT1 as a nuclear SIRT protein.
      supported_by:
        - reference_id: PMID:16079181
          supporting_text: three nuclear SIRT proteins (SIRT1, SIRT6, and
            SIRT7) show different subnuclear localizations
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: PMID:16079181
    negated: true
    review:
      summary: SIRT1 is not reported as nucleolar in this study.
      action: KEEP_AS_NON_CORE
      reason: Subnuclear localization is context-specific; NOT annotation kept
        as non-core.
      supported_by:
        - reference_id: PMID:16079181
          supporting_text: 2005 Aug 3. Evolutionarily conserved and nonconserved
            cellular localizations and functions of human SIRT proteins.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17172643
    review:
      summary: Generic protein binding is uninformative in this context.
      action: REMOVE
      reason: The study focuses on deacetylation by multiple HDACs rather than
        a specific binding interaction.
      supported_by:
        - reference_id: PMID:17172643
          supporting_text: HDAC1, HDAC3, HDAC10, SIRT1, and SIRT2 were involved in in vivo deacetylation.
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 functions as a transcriptional corepressor in multiple
        contexts.
      action: ACCEPT
      reason: Supported by multiple experimental studies of SIRT1 corepressor
        roles.
  - term:
      id: GO:0006642
      label: triglyceride mobilization
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 can influence triglyceride mobilization through
        deacetylation of metabolic regulators.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0009267
      label: cellular response to starvation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 responds to nutrient status via NAD+-dependent deacetylase
        activity and influences starvation responses.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic response rather than a core function.
  - term:
      id: GO:0031507
      label: heterochromatin formation
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: SirT1-mediated deacetylation supports heterochromatin
        formation.
      action: ACCEPT
      reason: Core chromatin silencing activity in this study.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1-mediated heterochromatin formation that
            includes deacetylation of histone tails
  - term:
      id: GO:0042393
      label: histone binding
    evidence_type: IPI
    original_reference_id: PMID:15469825
    review:
      summary: SIRT1 interacts with histone H1.
      action: ACCEPT
      reason: Histone interaction is part of the core chromatin regulation
        mechanism.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 interacts with and deacetylates histone H1 at
            lysine 26.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:15469825
    review:
      summary: Identical protein binding is not described in the PMID:15469825
        abstract.
      action: UNDECIDED
      reason: Need direct evidence for homomeric binding.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0045599
      label: negative regulation of fat cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences fat cell differentiation.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0050872
      label: white fat cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: SIRT1 influences white fat cell differentiation.
      action: KEEP_AS_NON_CORE
      reason: Downstream metabolic regulation rather than a core function.
  - term:
      id: GO:0002039
      label: p53 binding
    evidence_type: IPI
    original_reference_id: PMID:11672523
    review:
      summary: SIRT1 binds p53 as a deacetylation substrate.
      action: ACCEPT
      reason: Direct p53 binding is reported.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: binds and deacetylates the p53 protein with a
            specificity for its C-terminal Lys382 residue
  - term:
      id: GO:0003950
      label: NAD+ poly-ADP-ribosyltransferase activity
    evidence_type: TAS
    original_reference_id: PMID:17456799
    negated: true
    review:
      summary: Review notes that some sirtuins have ADP-ribosyltransferase
        activity but does not specify SIRT1.
      action: UNDECIDED
      reason: The reference does not provide SIRT1-specific evidence to support
        or refute this activity.
      supported_by:
        - reference_id: PMID:17456799
          supporting_text: Certain sirtuins have in addition an
            ADP-ribosyltransferase activity.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:11672523
    review:
      summary: SIRT1 is nuclear in cells where p53 deacetylation occurs.
      action: ACCEPT
      reason: Consistent with nuclear localization in SIRT1 studies.
      supported_by:
        - reference_id: PMID:20027304
          supporting_text: SIRT1 was localized both in cytoplasmic and nuclear
            compartments
  - term:
      id: GO:0005635
      label: nuclear envelope
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: Nuclear envelope localization is not described in the
        PMID:15469825 abstract.
      action: UNDECIDED
      reason: Insufficient evidence in this reference for nuclear envelope
        localization.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: PMID:15469825
    review:
      summary: Nucleolar localization is context-specific and not central to
        SIRT1 function.
      action: KEEP_AS_NON_CORE
      reason: Subnuclear localization is a downstream/context-specific aspect.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:15469825
    negated: true
    review:
      summary: This study does not report cytoplasmic localization; the NOT
        annotation is acceptable.
      action: ACCEPT
      reason: Consistent with the lack of cytoplasmic localization evidence in
        this reference.
      supported_by:
        - reference_id: PMID:15469825
          supporting_text: SirT1 deacetylates histone polypeptides with a
            preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9
            (H3-K9Ac) in vitro.
  - term:
      id: GO:0016605
      label: PML body
    evidence_type: IDA
    original_reference_id: PMID:12006491
    review:
      summary: SIRT1 localizes to PML nuclear bodies.
      action: ACCEPT
      reason: Direct localization to PML bodies is reported.
      supported_by:
        - reference_id: PMID:12006491
          supporting_text: SIRT1, the human Sir2 homolog, is recruited to the
            promyelocytic leukemia protein (PML) nuclear bodies
  - term:
      id: GO:0042127
      label: regulation of cell population proliferation
    evidence_type: IMP
    original_reference_id: PMID:12006491
    review:
      summary: SIRT1 rescues PML-induced premature senescence, indicating
        effects on cell proliferation state.
      action: KEEP_AS_NON_CORE
      reason: Senescence modulation is downstream and context-specific.
      supported_by:
        - reference_id: PMID:12006491
          supporting_text: rescues PML-mediated premature cellular senescence
  - term:
      id: GO:0043518
      label: negative regulation of DNA damage response, signal transduction by 
        p53 class mediator
    evidence_type: IDA
    original_reference_id: PMID:11672523
    review:
      summary: SIRT1 modulates p53-mediated DNA damage responses via
        deacetylation.
      action: KEEP_AS_NON_CORE
      reason: Downstream consequence of p53 regulation rather than core
        function.
      supported_by:
        - reference_id: PMID:11672523
          supporting_text: binds and deacetylates the p53 protein with a
            specificity for its C-terminal Lys382 residue
  - term:
      id: GO:0006476
      label: protein deacetylation
    evidence_type: IDA
    original_reference_id: PMID:18203716
    review:
      summary: SIRT1 deacetylates protein substrates such as WRN.
      action: ACCEPT
      reason: Direct deacetylation activity is reported.
      supported_by:
        - reference_id: PMID:18203716
          supporting_text: SIRT1 can deacetylate WRN both in vitro and in
            vivo.
  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IDA
    original_reference_id: PMID:18203716
    review:
      summary: SIRT1 regulates WRN-mediated responses to DNA damage.
      action: ACCEPT
      reason: DNA damage response is a supported functional role for SIRT1.
      supported_by:
        - reference_id: PMID:18203716
          supporting_text: SIRT1 regulates WRN-mediated cellular responses to
            DNA damage through deacetylation of WRN.
  - term:
      id: GO:0019213
      label: deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:18203716
    review:
      summary: SIRT1 deacetylates WRN.
      action: ACCEPT
      reason: Deacetylase activity is supported by direct substrate
        deacetylation.
      supported_by:
        - reference_id: PMID:18203716
          supporting_text: SIRT1 can deacetylate WRN both in vitro and in
            vivo.
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:16959573
    review:
      summary: Core NAD-dependent histone deacetylase activity demonstrated 
        experimentally.
      action: ACCEPT
      reason: Core molecular function. SIRT1 is a well-established NAD-dependent
        histone deacetylase.
      supported_by:
        - reference_id: PMID:16959573
          supporting_text: SIRT4 inhibits glutamate dehydrogenase and opposes 
            the effects of calorie restriction in pancreatic beta cells.
core_functions:
  - molecular_function:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    description: Primary enzymatic function of SIRT1. Catalyzes NAD-dependent 
      removal of acetyl groups from lysine residues of histones and numerous 
      non-histone proteins. The reaction couples NAD+ cleavage to lysine 
      deacetylation, producing nicotinamide and 2-O-acetyl-ADP-ribose.
  - molecular_function:
      id: GO:0046970
      label: histone H4K16 deacetylase activity, NAD-dependent
    description: Preferential histone substrate. Deacetylation of H4K16 is a 
      major activity of SIRT1 critical for heterochromatin formation and 
      transcriptional silencing.
  - molecular_function:
      id: GO:0046969
      label: histone H3K9 deacetylase activity, NAD-dependent
    description: Major histone substrate. H3K9 deacetylation is linked to 
      heterochromatin formation at rDNA and telomeric regions.
  - molecular_function:
      id: GO:0003714
      label: transcription corepressor activity
    description: SIRT1 functions as a transcriptional corepressor through 
      histone deacetylation and deacetylation of transcription factors.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on on
      inter-ontology links
    findings: []
  - id: GO_REF:0000116
    title: Automatic Gene Ontology annotation based on Rhea mapping
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:11672522
    title: Negative control of p53 by Sir2alpha promotes cell survival under 
      stress.
    findings: []
  - id: PMID:11672523
    title: hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.
    findings: []
  - id: PMID:12006491
    title: Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular 
      senescence.
    findings: []
  - id: PMID:12535671
    title: Human Sir2-related protein SIRT1 associates with the bHLH repressors 
      HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional 
      repression.
    findings: []
  - id: PMID:12837246
    title: Multiple tumor suppressor pathways negatively regulate telomerase.
    findings: []
  - id: PMID:14976264
    title: Stress-dependent regulation of FOXO transcription factors by the 
      SIRT1 deacetylase.
    findings: []
  - id: PMID:15126506
    title: FOXO4 is acetylated upon peroxide stress and deacetylated by the 
      longevity protein hSir2(SIRT1).
    findings: []
  - id: PMID:15152190
    title: Modulation of NF-kappaB-dependent transcription and cell survival by 
      the SIRT1 deacetylase.
    findings: []
  - id: PMID:15175761
    title: Sirt1 promotes fat mobilization in white adipocytes by repressing 
      PPAR-gamma.
    findings: []
  - id: PMID:15205477
    title: Calorie restriction promotes mammalian cell survival by inducing the 
      SIRT1 deacetylase.
    findings: []
  - id: PMID:15220471
    title: Silent information regulator 2 potentiates Foxo1-mediated 
      transcription through its deacetylase activity.
    findings: []
  - id: PMID:15469825
    title: Human SirT1 interacts with histone H1 and promotes formation of 
      facultative heterochromatin.
    findings: []
  - id: PMID:15632193
    title: SIRT1 deacetylation and repression of p300 involves lysine residues 
      1020/1024 within the cell cycle regulatory domain 1.
    findings: []
  - id: PMID:15684044
    title: Composition and histone substrates of polycomb repressive group 
      complexes change during cellular differentiation.
    findings: []
  - id: PMID:15692560
    title: Suppression of FOXO1 activity by FHL2 through SIRT1-mediated 
      deacetylation.
    findings: []
  - id: PMID:16079181
    title: Evolutionarily conserved and nonconserved cellular localizations and 
      functions of human SIRT proteins.
    findings: []
  - id: PMID:16892051
    title: Interactions between E2F1 and SirT1 regulate apoptotic response to 
      DNA damage.
    findings: []
  - id: PMID:16959573
    title: SIRT4 inhibits glutamate dehydrogenase and opposes the effects of 
      calorie restriction in pancreatic beta cells.
    findings: []
  - id: PMID:16998810
    title: SIRT1 interacts with p73 and suppresses p73-dependent transcriptional
      activity.
    findings: []
  - id: PMID:17172643
    title: Multiple histone deacetylases and the CREB-binding protein regulate 
      pre-mRNA 3'-end processing.
    findings: []
  - id: PMID:17317627
    title: Phosphorylation of HuR by Chk2 regulates SIRT1 expression.
    findings: []
  - id: PMID:17334224
    title: SIRT1 promotes DNA repair activity and deacetylation of Ku70.
    findings: []
  - id: PMID:17456799
    title: Sirtuin functions in health and disease.
    findings: []
  - id: PMID:17505061
    title: Sirtuin 1 is required for antagonist-induced transcriptional 
      repression of androgen-responsive genes by the androgen receptor.
    findings: []
  - id: PMID:17612497
    title: SIRT1 regulates the function of the Nijmegen breakage syndrome 
      protein.
    findings: []
  - id: PMID:17680780
    title: Sirt1 interacts with transducin-like enhancer of split-1 to inhibit 
      nuclear factor kappaB-mediated transcription.
    findings: []
  - id: PMID:17901049
    title: The direct involvement of SirT1 in insulin-induced insulin receptor 
      substrate-2 tyrosine phosphorylation.
    findings: []
  - id: PMID:17916362
    title: Sirt1 modulates premature senescence-like phenotype in human 
      endothelial cells.
    findings: []
  - id: PMID:17936707
    title: SIRT1 deacetylates and positively regulates the nuclear receptor LXR.
    findings: []
  - id: PMID:17964266
    title: Active regulator of SIRT1 cooperates with SIRT1 and facilitates 
      suppression of p53 activity.
    findings: []
  - id: PMID:18004385
    title: SIRT1 regulates the histone methyl-transferase SUV39H1 during 
      heterochromatin formation.
    findings: []
  - id: PMID:18203716
    title: Regulation of WRN protein cellular localization and enzymatic 
      activities by SIRT1-mediated deacetylation.
    findings: []
  - id: PMID:18235501
    title: DBC1 is a negative regulator of SIRT1.
    findings: []
  - id: PMID:18235502
    title: Negative regulation of the deacetylase SIRT1 by DBC1.
    findings: []
  - id: PMID:18296641
    title: A role for the NAD-dependent deacetylase Sirt1 in the regulation of 
      autophagy.
    findings: []
  - id: PMID:18485871
    title: Epigenetic control of rDNA loci in response to intracellular energy 
      status.
    findings: []
  - id: PMID:18662546
    title: SIRT1 regulates circadian clock gene expression through PER2 
      deacetylation.
    findings: []
  - id: PMID:18687677
    title: SIRT1 modulation of the acetylation status, cytosolic localization, 
      and activity of LKB1. Possible role in AMP-activated protein kinase 
      activation.
    findings: []
  - id: PMID:19047049
    title: Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates 
      beta-catenin signaling and NFkappaB-specific transcription activity 
      leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast 
      tumor cells.
    findings: []
  - id: PMID:19188449
    title: hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in
      response to DNA damage.
    findings: []
  - id: PMID:19236849
    title: Carboxy-terminal phosphorylation of SIRT1 by protein kinase CK2.
    findings: []
  - id: PMID:19343720
    title: 'Identification and characterization of proteins interacting with SIRT1
      and SIRT3: implications in the anti-aging and metabolic effects of sirtuins.'
    findings: []
  - id: PMID:19478080
    title: Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target
      gene promoters.
    findings: []
  - id: PMID:19680552
    title: CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase
      activity and cellular response to DNA-damage.
    findings: []
  - id: PMID:19690166
    title: Transcriptional corepressor SMILE recruits SIRT1 to inhibit nuclear 
      receptor estrogen receptor-related receptor gamma transactivation.
    findings: []
  - id: PMID:19934257
    title: SIRT1 deacetylates APE1 and regulates cellular base excision repair.
    findings: []
  - id: PMID:19934264
    title: 'Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity:
      implication in the retinoic acid-induced neuronal differentiation of P19 cells.'
    findings: []
  - id: PMID:20027304
    title: JNK1 phosphorylates SIRT1 and promotes its enzymatic activity.
    findings: []
  - id: PMID:20074560
    title: Repression of estrogen receptor beta function by putative tumor 
      suppressor DBC1.
    findings: []
  - id: PMID:20097625
    title: Role of SIRT1 in homologous recombination.
    findings: []
  - id: PMID:20100829
    title: SIRT1 regulates autoacetylation and histone acetyltransferase 
      activity of TIP60.
    findings: []
  - id: PMID:20167603
    title: DYRK1A and DYRK3 promote cell survival through phosphorylation and 
      activation of SIRT1.
    findings: []
  - id: PMID:20169165
    title: SIRT1 negatively regulates the mammalian target of rapamycin.
    findings: []
  - id: PMID:20203304
    title: SIRT1 promotes proliferation and prevents senescence through 
      targeting LKB1 in primary porcine aortic endothelial cells.
    findings: []
  - id: PMID:20375098
    title: Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to
      inhibit LRH-1 transactivation.
    findings: []
  - id: PMID:20424141
    title: MicroRNA-34a induces endothelial progenitor cell senescence and 
      impedes its angiogenesis via suppressing silent information regulator 1.
    findings: []
  - id: PMID:20439735
    title: SIRT1 regulates Dishevelled proteins and promotes transient and 
      constitutive Wnt signaling.
    findings: []
  - id: PMID:20620956
    title: Sirtuin 1 modulates cellular responses to hypoxia by deacetylating 
      hypoxia-inducible factor 1alpha.
    findings: []
  - id: PMID:20660480
    title: SIRT1 is regulated by a PPAR{γ}-SIRT1 negative feedback loop 
      associated with senescence.
    findings: []
  - id: PMID:20670893
    title: SIRT1 regulates UV-induced DNA repair through deacetylating XPA.
    findings: []
  - id: PMID:20817729
    title: SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of 
      hepatic lipid metabolism.
    findings: []
  - id: PMID:20955178
    title: Regulation of unfolded protein response modulator XBP1s by 
      acetylation and deacetylation.
    findings: []
  - id: PMID:21030595
    title: HDAC3 is negatively regulated by the nuclear protein DBC1.
    findings: []
  - id: PMID:21081649
    title: SIRT2 regulates NF-κB dependent gene expression through deacetylation
      of p65 Lys310.
    findings: []
  - id: PMID:21149730
    title: Regulation of global genome nucleotide excision repair by SIRT1 
      through xeroderma pigmentosum C.
    findings: []
  - id: PMID:21212262
    title: MST1 promotes apoptosis through regulating Sirt1-dependent p53 
      deacetylation.
    findings: []
  - id: PMID:21241768
    title: Phosphoinositide 3-kinase as a novel functional target for the 
      regulation of the insulin signaling pathway by SIRT1.
    findings: []
  - id: PMID:21245319
    title: Methyltransferase Set7/9 regulates p53 activity by interacting with 
      Sirtuin 1 (SIRT1).
    findings: []
  - id: PMID:21471201
    title: Cancer cell survival following DNA damage-mediated premature 
      senescence is regulated by mammalian target of rapamycin (mTOR)-dependent 
      Inhibition of sirtuin 1.
    findings: []
  - id: PMID:21555002
    title: EVI1 up-regulates the stress responsive gene SIRT1 which triggers 
      deacetylation and degradation of EVI1.
    findings: []
  - id: PMID:21698133
    title: SIRT1 promotes N-Myc oncogenesis through a positive feedback loop 
      involving the effects of MKP3 and ERK on N-Myc protein stability.
    findings: []
  - id: PMID:21775285
    title: The deacetylase SIRT1 promotes membrane localization and activation 
      of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.
    findings: []
  - id: PMID:21807113
    title: Sirt1 deacetylates c-Myc and promotes c-Myc/Max association.
    findings: []
  - id: PMID:21841822
    title: Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3
      ubiquitination and degradation.
    findings: []
  - id: PMID:21890893
    title: SIRT1 links CIITA deacetylation to MHC II activation.
    findings: []
  - id: PMID:21909281
    title: The evolutionarily conserved longevity determinants HCF-1 and 
      SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.
    findings: []
  - id: PMID:21947282
    title: SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and 
      alters its activities.
    findings: []
  - id: PMID:21968188
    title: p53 deacetylation by SIRT1 decreases during protein kinase CKII 
      downregulation-mediated cellular senescence.
    findings: []
  - id: PMID:22094255
    title: Oxidative damage targets complexes containing DNA methyltransferases,
      SIRT1, and polycomb members to promoter CpG Islands.
    findings: []
  - id: PMID:22169038
    title: SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory
      drive.
    findings: []
  - id: PMID:22190034
    title: Global landscape of HIV-human protein complexes.
    findings: []
  - id: PMID:22510882
    title: Novel repressor regulates insulin sensitivity through interaction 
      with Foxo1.
    findings: []
  - id: PMID:22863012
    title: Brown remodeling of white adipose tissue by SirT1-dependent 
      deacetylation of Pparγ.
    findings: []
  - id: PMID:22918831
    title: Autoacetylation of the MYST lysine acetyltransferase MOF protein.
    findings: []
  - id: PMID:22956909
    title: Dynamic distribution of linker histone H1.5 in cellular 
      differentiation.
    findings: []
  - id: PMID:23056314
    title: Angiogenesis inhibitor vasohibin-1 enhances stress resistance of 
      endothelial cells via induction of SOD2 and SIRT1.
    findings: []
  - id: PMID:23142079
    title: The deacetylase Sirt6 activates the acetyltransferase GCN5 and 
      suppresses hepatic gluconeogenesis.
    findings: []
  - id: PMID:23382074
    title: A high-confidence interaction map identifies SIRT1 as a mediator of 
      acetylation of USP22 and the SAGA coactivator complex.
    findings: []
  - id: PMID:23960241
    title: MicroRNA-mediated epigenetic silencing of sirtuin1 contributes to 
      impaired angiogenic responses.
    findings: []
  - id: PMID:24043310
    title: SIRT4 represses peroxisome proliferator-activated receptor α activity
      to suppress hepatic fat oxidation.
    findings: []
  - id: PMID:24048733
    title: Antidicer RNAse activity of monocyte chemotactic protein-induced 
      protein-1 is critical for inducing angiogenesis.
    findings: []
  - id: PMID:24681097
    title: AROS has a context-dependent effect on SIRT1.
    findings: []
  - id: PMID:24824780
    title: MCC inhibits beta-catenin transcriptional activity by sequestering 
      DBC1 in the cytoplasm.
    findings: []
  - id: PMID:25217442
    title: Vascular importance of the miR-212/132 cluster.
    findings: []
  - id: PMID:25661920
    title: CCAR2 negatively regulates nuclear receptor LXRα by competing with 
      SIRT1 deacetylase.
    findings: []
  - id: PMID:25751424
    title: NAD(+)-SIRT1 control of H3K4 trimethylation through circadian 
      deacetylation of MLL1.
    findings: []
  - id: PMID:28497810
    title: 'Class I histone deacetylases are major histone decrotonylases: evidence
      for critical and broad function of histone crotonylation in transcription.'
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:29656858
    title: A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes 
      Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism,
      and Cerebellar Dysgenesis.
    findings: []
  - id: PMID:29681526
    title: A Designed Peptide Targets Two Types of Modifications of p53 with 
      Anti-cancer Activity.
    findings: []
  - id: PMID:29765047
    title: Tip60-mediated lipin 1 acetylation and ER translocation determine 
      triacylglycerol synthesis rate.
    findings: []
  - id: PMID:30193097
    title: Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Toggles 
      Enzyme Activity between Gluconeogenic and Anaplerotic Reactions.
    findings: []
  - id: PMID:30409912
    title: Dynamic acetylation of the kinetochore-associated protein HEC1 
      ensures accurate microtubule-kinetochore attachment.
    findings: []
  - id: PMID:31403225
    title: The interactome of KRAB zinc finger proteins reveals the evolutionary
      history of their functional diversification.
    findings: []
  - id: PMID:31722219
    title: CCDC84 Acetylation Oscillation Regulates Centrosome Duplication by 
      Modulating HsSAS-6 Degradation.
    findings: []
  - id: PMID:32034146
    title: Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly 
      and activation.
    findings: []
  - id: PMID:32538779
    title: Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and 
      potentiates the DNA damage response and repair in humans and mice.
    findings: []
  - id: PMID:32761762
    title: CSAG2 is a cancer-specific activator of SIRT1.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:38512451
    title: The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to
      promote YAP signaling in gastric cancer.
    findings: []
  - id: Reactome:R-HSA-3371453
    title: Regulation of HSF1-mediated heat shock response
    findings: []
  - id: Reactome:R-HSA-3371467
    title: SIRT1 deacetylates HSF1
    findings: []
  - id: Reactome:R-HSA-3371518
    title: SIRT1 binds to HSF1
    findings: []
  - id: Reactome:R-HSA-3371537
    title: DBC1 binds SIRT1
    findings: []
  - id: Reactome:R-HSA-427359
    title: SIRT1 negatively regulates rRNA expression
    findings: []
  - id: Reactome:R-HSA-427514
    title: eNoSC deacetylates histone H3
    findings: []
  - id: Reactome:R-HSA-427527
    title: eNoSC dimethylates histone H3 at lysine-9
    findings: []
  - id: Reactome:R-HSA-427528
    title: Formation of energy-dependent Nucleolar Silencing Complex (eNoSC)
    findings: []
  - id: Reactome:R-HSA-9620532
    title: SIRT1,SIRT3 deacetylate FOXO3
    findings: []
  - id: Reactome:R-HSA-9765850
    title: ZEB1 recruits MPHOSPH8 (MPP8) to CDH1 gene promoter
    findings: []
  - id: Reactome:R-HSA-9825772
    title: SIRT1 deacetylates HINT1 dimer
    findings: []
  - id: Reactome:R-HSA-9854916
    title: MITF-M-dependent SIRT1 gene expression
    findings: []
  - id: file:human/SIRT1/SIRT1-deep-research-falcon.md
    title: Deep research report on SIRT1
    findings: []

SIRT1

Gene Description

Existing Annotations Review

Core Functions

Primary enzymatic function of SIRT1. Catalyzes NAD-dependent removal of acetyl groups from lysine residues of histones and numerous non-histone proteins. The reaction couples NAD+ cleavage to lysine deacetylation, producing nicotinamide and 2-O-acetyl-ADP-ribose.

Preferential histone substrate. Deacetylation of H4K16 is a major activity of SIRT1 critical for heterochromatin formation and transcriptional silencing.

Major histone substrate. H3K9 deacetylation is linked to heterochromatin formation at rDNA and telomeric regions.

SIRT1 functions as a transcriptional corepressor through histone deacetylation and deacetylation of transcription factors.

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

Bioreason Rl Review

BioReason-Pro RL Review: SIRT1 (human)

Functional Summary Review

Notes on thinking trace

📄 View Raw YAML