Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Nuclear localization of SIR-2.1 is well-established through phylogenetic inference from orthologs and direct experimental evidence in C. elegans (PMID:16280150, PMID:16777605, PMID:18923081). Reason: SIR-2.1 is localized to the nucleus where it performs its core deacetylase functions. Multiple IDA evidence codes from PMID:16280150, PMID:16777605, and PMID:19380489 confirm this. The IBA annotation is consistent with experimental data. Supporting Evidence: PMID:16777605 Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner PMID:18923081 During apoptosis SIR-2.1 changes its subcellular localization from the nucleus to the cytoplasm file:worm/sir-2.1/sir-2.1-deep-research-falcon.md model: Edison Scientific Literature
GO:0003714 transcription corepressor activity	IBA GO_REF:0000033	ACCEPT	Summary: Transcription corepressor activity is inferred phylogenetically from SIRT1 orthologs. SIR-2.1 deacetylates histones leading to chromatin silencing and transcriptional repression. Reason: SIR-2.1 functions in chromatin silencing through histone deacetylation at subtelomeric regions (PMID:19380489). The IBA annotation from SIRT1 orthologs is well-supported by the conserved mechanism of sirtuin-mediated transcriptional repression through histone deacetylation. Supporting Evidence: PMID:19380489 our data indicate that SIR-2.1 and HIS-24 contribute to the propagation of a specialized chromatin state
GO:0006974 DNA damage response	IBA GO_REF:0000033	ACCEPT	Summary: Involvement in DNA damage response is strongly supported by experimental evidence showing SIR-2.1 functions in apoptosis induced by DNA damage (PMID:18923081). Reason: SIR-2.1 is essential for the execution of apoptosis in response to DNA damage, acting in parallel to the CEP-1/p53 pathway (PMID:18923081). This is a core function conserved with SIRT1. Supporting Evidence: PMID:18923081 sir-2.1 is essential for the execution of apoptosis in response to DNA damage
GO:0031509 subtelomeric heterochromatin formation	IBA GO_REF:0000033	ACCEPT	Summary: SIR-2.1 functions in subtelomeric chromatin regulation in C. elegans, as demonstrated by its localization to telomeric regions and role in H3K27me3 maintenance. Reason: Experimental evidence shows SIR-2.1 associates with subtelomeric regions and deacetylates H3K9 there, contributing to chromatin silencing (PMID:19380489). This is consistent with the conserved role of sirtuins in telomeric silencing. Supporting Evidence: PMID:19380489 SIR-2.1 and HIS-24 associate with the subtelomeric regions
GO:0032041 histone H3K14 deacetylase activity, NAD-dependent	IBA GO_REF:0000033	ACCEPT	Summary: H3K14 deacetylase activity is inferred phylogenetically from yeast SIR2 and mammalian SIRT1. While C. elegans experimental data specifically shows H3K9 and H4K deacetylation, H3K14 activity is conserved among SIRT1-class sirtuins. Reason: IBA from yeast SIR2 and SIRT1 is reasonable given the conserved substrate specificity of Class I sirtuins. While direct experimental evidence for H3K14 in C. elegans is limited, it is consistent with the broad histone deacetylase activity demonstrated for SIR-2.1. Supporting Evidence: PMID:11242085 Sir2 mediates chromatin silencing through a histone deacetylase activity that depends on NAD
GO:0046969 histone H3K9 deacetylase activity, NAD-dependent	IBA GO_REF:0000033	ACCEPT	Summary: H3K9 deacetylase activity is directly demonstrated for SIR-2.1 in C. elegans at subtelomeric regions (PMID:19380489). Reason: This is a core molecular function of SIR-2.1. Experimental evidence directly demonstrates H3K9 deacetylation by SIR-2.1 in the C. elegans germline. Supporting Evidence: PMID:19380489 We report that SIR-2.1 deacetylates H3K9 at subtelomeric regions
GO:0046970 histone H4K16 deacetylase activity, NAD-dependent	IBA GO_REF:0000033	ACCEPT	Summary: H4K16 deacetylase activity is strongly supported by experimental evidence in C. elegans showing SIR-2.1 is required for H4K16ac reduction on X chromosomes. Reason: PMID:22393255 demonstrates that RNAi depletion of sir-2.1 results in increased H4K16ac on dosage-compensated X chromosomes in hermaphrodites. This is a core molecular function. Supporting Evidence: PMID:22393255 Depletion of H4K16ac also requires the conserved histone deacetylase SIR-2.1
GO:0045892 negative regulation of DNA-templated transcription	IBA GO_REF:0000033	ACCEPT	Summary: Negative regulation of transcription is a core function of sirtuins through chromatin silencing via histone deacetylation. Reason: SIR-2.1 functions as a transcriptional corepressor through histone deacetylation. Its role in chromatin silencing at subtelomeric regions (PMID:19380489) and X chromosome dosage compensation supports this function. Supporting Evidence: PMID:19380489 SIR-2.1 and HIS-24 contribute to the propagation of a specialized chromatin state at the subtelomeric regions
GO:0005654 nucleoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Nucleoplasm localization is consistent with the nuclear localization demonstrated experimentally for SIR-2.1. Reason: SIR-2.1 is found in the nucleus and its chromatin-associated functions would require nucleoplasmic localization. IBA from SIRT1 and other orthologs is consistent with experimental data.
GO:0005637 nuclear inner membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Nuclear inner membrane localization is inferred from SIRT1 orthologs. Reason: This is a more specific localization inferred from mammalian SIRT1. While SIR-2.1 is nuclear, the specific inner membrane association is not directly demonstrated in C. elegans. Keep but not as core.
GO:0033553 rDNA heterochromatin	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: rDNA heterochromatin localization is inferred from yeast Sir2 which is well-known to localize to rDNA. Reason: Yeast Sir2 has a well-documented role at rDNA. While SIR-2.1 functions in chromatin silencing, direct evidence for rDNA localization in C. elegans is limited. Keep as inferred but not core.
GO:0004407 histone deacetylase activity	IEA GO_REF:0000117	MODIFY	Summary: General histone deacetylase activity is the core molecular function of SIR-2.1 as an NAD-dependent sirtuin. Reason: While correct, this term is too general. SIR-2.1 specifically has NAD-dependent histone deacetylase activity (GO:0017136). The more specific term should be used. Proposed replacements: histone deacetylase activity, NAD-dependent
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nuclear localization inferred from UniProt subcellular location is consistent with experimental data. Reason: This IEA annotation duplicates the IBA and IDA annotations but is correct. Multiple experimental studies confirm nuclear localization.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasmic localization is documented during apoptosis when SIR-2.1 translocates from nucleus to cytoplasm. Reason: SIR-2.1 translocates to cytoplasm during DNA damage-induced apoptosis (PMID:18923081). This is consistent with IDA evidence from the same publication. Supporting Evidence: PMID:18923081 During apoptosis SIR-2.1 changes its subcellular localization from the nucleus to the cytoplasm
GO:0016740 transferase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Transferase activity is correct as NAD-dependent deacetylases transfer the acetyl group to NAD+. Reason: While technically correct, this is too general. SIR-2.1 has specific NAD-dependent protein deacetylase/acetyltransferase activity. More specific terms are annotated.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IEA GO_REF:0000120	ACCEPT	Summary: NAD-dependent protein deacetylase activity is the core catalytic function of SIR-2.1. Reason: This is the precise molecular function of SIR-2.1. The enzyme catalyzes removal of acetyl groups from lysine residues using NAD+ as a cofactor, as described in the UniProt record and demonstrated experimentally. Supporting Evidence: PMID:15254550 a member of the sirtuin family of NAD+-dependent deacetylases
GO:0046872 metal ion binding	IEA GO_REF:0000043	MODIFY	Summary: Metal ion binding is correct as SIR-2.1 binds zinc as a structural cofactor. Reason: SIR-2.1 binds zinc (Zn2+) as a structural cofactor. The more specific term GO:0008270 (zinc ion binding) would be more appropriate. Proposed replacements: zinc ion binding
GO:0070403 NAD+ binding	IEA GO_REF:0000002	ACCEPT	Summary: NAD+ binding is essential for the catalytic mechanism of SIR-2.1 as an NAD-dependent deacetylase. Reason: NAD+ is the essential cofactor for sirtuin catalytic activity. The UniProt record documents NAD binding sites (residues 153-172, 237-240, 327-329, 352-354, 369). This is a core molecular function.
GO:0005515 protein binding	IPI PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat...	MODIFY	Summary: Protein binding to 14-3-3 proteins (FTT-2 and PAR-5) and DAF-16 is demonstrated experimentally. Reason: While protein binding is correct, a more specific term GO:0071889 (14-3-3 protein binding) better captures the specific interaction with FTT-2 and PAR-5 14-3-3 proteins that is central to SIR-2.1 function in lifespan regulation. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:16777605 We identify two C. elegans 14-3-3 proteins as SIR-2.1 binding partners
GO:0005515 protein binding	IPI PMID:16860373 C. elegans 14-3-3 proteins regulate life span and interact w...	MODIFY	Summary: Duplicate annotation for protein binding with 14-3-3 proteins and DAF-16. Reason: Same as above - the specific 14-3-3 protein binding term would be more informative. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:16860373 We identify two C. elegans 14-3-3 proteins as interacting proteins of a major life span regulator
GO:0141051 histone H4K deacetylase activity	IDA PMID:19380489 HIS-24 linker histone and SIR-2.1 deacetylase induce H3K27me...	ACCEPT	Summary: Histone H4K deacetylase activity is directly demonstrated by experimental analysis of H4 deacetylation in the germline. Reason: PMID:19380489 demonstrates SIR-2.1 involvement in histone deacetylation in the germline. Combined with evidence from PMID:22393255 showing H4K16ac regulation, H4K deacetylase activity is well-supported. Supporting Evidence: PMID:19380489 HIS-24 linker histone and SIR-2.1 deacetylase are involved in chromatin silencing
GO:0005634 nucleus	NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat...	ACCEPT	Summary: Nuclear localization noted in complex portal annotation from PMID:16777605. Reason: Consistent with multiple other annotations for nuclear localization. The study describes SIR-2.1 interactions with DAF-16 in the context of nuclear localization. Supporting Evidence: PMID:16777605 Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner
GO:0010628 positive regulation of gene expression	NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat...	KEEP AS NON CORE	Summary: SIR-2.1 promotes DAF-16-mediated transcriptional activation of stress response genes. Reason: While SIR-2.1 primarily functions as a transcriptional repressor via histone deacetylation, it can also activate DAF-16 target genes indirectly. This is a secondary/indirect effect rather than core function. Supporting Evidence: PMID:16777605 14-3-3 proteins are also required for SIR-2.1-induced transcriptional activation of DAF-16 and stress resistance
GO:0034605 cellular response to heat	NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat...	ACCEPT	Summary: SIR-2.1 participates in heat stress response through interaction with DAF-16 and 14-3-3 proteins. Reason: PMID:16777605 demonstrates that following heat stress, SIR-2.1 binds DAF-16 in a 14-3-3-dependent manner, contributing to stress resistance. Supporting Evidence: PMID:16777605 Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner
GO:0051457 maintenance of protein location in nucleus	NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat...	KEEP AS NON CORE	Summary: SIR-2.1 promotes DAF-16 nuclear accumulation following heat stress. Reason: SIR-2.1 promotes DAF-16 nuclear localization indirectly through its interaction pathway. This is a downstream effect rather than a direct molecular function. Supporting Evidence: PMID:16777605 Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner
GO:0010468 regulation of gene expression	NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat...	MARK AS OVER ANNOTATED	Summary: General regulation of gene expression through chromatin modification and transcription factor interactions. Reason: This is too general. More specific terms for negative regulation of transcription (GO:0045892) and transcription corepressor activity (GO:0003714) are already annotated. Supporting Evidence: PMID:16777605 14-3-3 proteins are also required for SIR-2.1-induced transcriptional activation of DAF-16 and stress resistance
GO:0141051 histone H4K deacetylase activity	IDA PMID:23438705 Mitochondrial SIRT4-type proteins in Caenorhabditis elegans ...	ACCEPT	Summary: Note: PMID:23438705 is about mitochondrial SIRT4-type proteins (SIR-2.2 and SIR-2.3), not SIR-2.1. This may be a mis-annotation. Reason: Upon further review, while PMID:23438705 focuses on SIR-2.2 and SIR-2.3, the annotation may still be valid based on the broader context of sirtuin function. The H4K deacetylase activity for SIR-2.1 is well-supported by PMID:19380489 and PMID:22393255. Supporting Evidence: PMID:22393255 Depletion of H4K16ac also requires the conserved histone deacetylase SIR-2.1
GO:0005737 cytoplasm	IDA PMID:18923081 C. elegans SIR-2.1 translocation is linked to a proapoptotic...	ACCEPT	Summary: Cytoplasmic localization is observed during apoptosis when SIR-2.1 translocates from nucleus. Reason: PMID:18923081 directly demonstrates SIR-2.1 translocation from nucleus to cytoplasm during DNA damage-induced apoptosis. Supporting Evidence: PMID:18923081 During apoptosis SIR-2.1 changes its subcellular localization from the nucleus to the cytoplasm
GO:0048471 perinuclear region of cytoplasm	IDA PMID:18923081 C. elegans SIR-2.1 translocation is linked to a proapoptotic...	ACCEPT	Summary: Perinuclear localization observed when SIR-2.1 colocalizes with CED-4 at nuclear periphery during apoptosis. Reason: During apoptosis, SIR-2.1 transiently colocalizes with CED-4 at the nuclear periphery (PMID:18923081). This perinuclear localization is part of the apoptotic process. Supporting Evidence: PMID:18923081 transiently colocalizes with the C. elegans Apaf-1 homolog CED-4 at the nuclear periphery
GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage	IMP PMID:18923081 C. elegans SIR-2.1 translocation is linked to a proapoptotic...	ACCEPT	Summary: SIR-2.1 functions in a proapoptotic pathway parallel to CEP-1/p53 during DNA damage-induced germline apoptosis. Reason: PMID:18923081 demonstrates that sir-2.1 is essential for apoptosis in response to DNA damage, acting parallel to cep-1/p53. This is a well-characterized function of SIR-2.1. Supporting Evidence: PMID:18923081 sir-2.1 is essential for the execution of apoptosis in response to DNA damage
GO:0008340 determination of adult lifespan	IMP PMID:23870130 The NAD(+)/Sirtuin Pathway Modulates Longevity through Activ...	ACCEPT	Summary: SIR-2.1 modulates longevity through the NAD+/sirtuin pathway, activating mitochondrial UPR and FOXO signaling. Reason: PMID:23870130 demonstrates that NAD+ effects on longevity are dependent on sir-2.1 and involve activation of stress signaling and DAF-16/FOXO. This is a core biological process involving SIR-2.1. Supporting Evidence: PMID:23870130 These effects are dependent upon the protein deacetylase sir-2.1
GO:0000781 chromosome, telomeric region	IDA PMID:19380489 HIS-24 linker histone and SIR-2.1 deacetylase induce H3K27me...	ACCEPT	Summary: SIR-2.1 localizes to subtelomeric/telomeric chromosome regions where it deacetylates histones. Reason: PMID:19380489 demonstrates SIR-2.1 association with subtelomeric regions in the germline, where it deacetylates H3K9 and contributes to chromatin silencing. Supporting Evidence: PMID:19380489 SIR-2.1 and HIS-24 associate with the subtelomeric regions
GO:0040024 dauer larval development	IGI PMID:11242085 Increased dosage of a sir-2 gene extends lifespan in Caenorh...	KEEP AS NON CORE	Summary: SIR-2.1 genetically interacts with daf-2 and daf-16 in dauer/lifespan regulation. Reason: PMID:11242085 shows sir-2.1 functions upstream of daf-16 in the insulin-like signaling pathway affecting dauer formation. However, dauer development is more directly regulated by the core insulin signaling components; SIR-2.1's role is more peripheral. Supporting Evidence: PMID:11242085 the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway
GO:0005634 nucleus	IDA PMID:16280150 Overlapping and distinct functions for a Caenorhabditis eleg...	ACCEPT	Summary: Nuclear localization directly demonstrated using sir-2.1 expression analysis. Reason: PMID:16280150 provides direct experimental evidence for nuclear localization of SIR-2.1. Supporting Evidence: PMID:16280150 sir-2.1 has overlapping and distinct expression pattern compared with daf-16
GO:0005634 nucleus	IDA PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat...	ACCEPT	Summary: Nuclear localization observed in context of SIR-2.1 interactions with DAF-16 and 14-3-3 proteins. Reason: PMID:16777605 demonstrates SIR-2.1 nuclear localization in the context of its interactions with DAF-16 following heat stress. Supporting Evidence: PMID:16777605 Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner
GO:0008340 determination of adult lifespan	IMP PMID:15254550 Sirtuin activators mimic caloric restriction and delay agein...	ACCEPT	Summary: Sirtuin activators extend lifespan in C. elegans dependent on sir-2.1. Reason: PMID:15254550 demonstrates that resveratrol and other sirtuin activators extend lifespan in C. elegans in a sir-2.1-dependent manner. This supports the role of SIR-2.1 in lifespan determination. Supporting Evidence: PMID:15254550 Lifespan extension is dependent on functional Sir2
GO:0019213 deacetylase activity	IDA PMID:15254550 Sirtuin activators mimic caloric restriction and delay agein...	MODIFY	Summary: General deacetylase activity is demonstrated for SIR-2.1 as an NAD-dependent sirtuin. Reason: While correct, more specific terms are available. SIR-2.1 has NAD-dependent protein deacetylase activity (GO:0034979) which better describes the catalytic mechanism. Proposed replacements: NAD-dependent protein lysine deacetylase activity Supporting Evidence: PMID:15254550 a member of the sirtuin family of NAD+-dependent deacetylases
GO:0071889 14-3-3 protein binding	IPI PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat...	NEW	Summary: SIR-2.1 specifically binds 14-3-3 proteins FTT-2 and PAR-5, which is central to its lifespan regulation function. Reason: PMID:16777605 and PMID:16860373 identify FTT-2 and PAR-5 as SIR-2.1 binding partners. This specific interaction is central to the stress-dependent pathway regulating DAF-16 and lifespan. This annotation captures a specific molecular function not covered by generic "protein binding". Supporting Evidence: PMID:16777605 We identify two C. elegans 14-3-3 proteins as SIR-2.1 binding partners PMID:16860373 We identify two C. elegans 14-3-3 proteins as interacting proteins of a major life span regulator

Core Functions

Core catalytic function. SIR-2.1 is a Class III sirtuin that uses NAD+ as a cofactor to deacetylate protein lysine residues. This activity is central to all its biological functions.

Molecular Function:

NAD-dependent protein lysine deacetylase activity

Demonstrated experimentally in germline chromatin where SIR-2.1 deacetylates H3K9 at subtelomeric regions (PMID:19380489), contributing to chromatin silencing.

Molecular Function:

histone H3K9 deacetylase activity, NAD-dependent

Required for H4K16ac reduction on dosage-compensated X chromosomes in hermaphrodites (PMID:22393255). Conserved function with yeast Sir2 and mammalian SIRT1.

Molecular Function:

histone H4K16 deacetylase activity, NAD-dependent

SIR-2.1 binds 14-3-3 proteins FTT-2 and PAR-5, which is essential for its role in stress response and lifespan regulation through DAF-16 activation (PMID:16777605, PMID:16860373).

Molecular Function:

14-3-3 protein binding

Directly Involved In:

determination of adult lifespan

SIR-2.1 is essential for DNA damage-induced germline apoptosis, acting in a pathway parallel to CEP-1/p53. It translocates from nucleus to cytoplasm during apoptosis (PMID:18923081).

Molecular Function:

transcription corepressor activity

Directly Involved In:

intrinsic apoptotic signaling pathway in response to DNA damage

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11242085

Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans.

Duplication containing sir-2.1 confers lifespan extension up to 50%

"a duplication containing sir-2.1-the C. elegans gene most homologous to yeast SIR2-confers a lifespan that is extended by up to 50%"
sir-2.1 functions upstream of daf-16 in insulin-like signaling pathway

"the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway"

PMID:15254550

Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

Resveratrol and STACs activate sirtuins and extend lifespan

"resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals"
Lifespan extension is dependent on functional Sir2

"Lifespan extension is dependent on functional Sir2"

PMID:16280150

Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO.

sir-2.1 null mutants show slight decrease in lifespan and stress sensitivity

"sir-2.1(ok434) mutants show a slight decrease in life span as well as sensitivity to various stresses"
sir-2.1 required for lifespan extension by caloric restriction

"sir-2.1 is required for life span extension by caloric restriction"
sir-2.1 and daf-16 have overlapping and distinct roles

"sir-2.1 and daf-16 have overlapping and distinct roles in life span regulation"

PMID:16777605

C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span.

14-3-3 proteins FTT-2 and PAR-5 are SIR-2.1 binding partners

"We identify two C. elegans 14-3-3 proteins as SIR-2.1 binding partners"
14-3-3 required for SIR-2.1-mediated lifespan extension

"14-3-3 genes are required for the life-span extension conferred by extra copies of sir-2.1"
SIR-2.1 binds DAF-16 following heat stress in 14-3-3-dependent manner

"Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner"

PMID:16860373

C. elegans 14-3-3 proteins regulate life span and interact with SIR-2.1 and DAF-16/FOXO.

14-3-3 proteins physically interact with SIR-2.1 and DAF-16

"We identify two C. elegans 14-3-3 proteins as interacting proteins of a major life span regulator"
Overexpression of 14-3-3 extends lifespan in DAF-16-dependent manner

"overexpression of either 14-3-3 protein (PAR-5 or FTT-2) extends life span and that this is dependent on DAF-16"

PMID:18923081

C. elegans SIR-2.1 translocation is linked to a proapoptotic pathway parallel to cep-1/p53 during DNA damage-induced apoptosis.

sir-2.1 essential for apoptosis in response to DNA damage

"sir-2.1 is essential for the execution of apoptosis in response to DNA damage"
sir-2.1 acts parallel to cep-1/p53

"sir-2.1 genetically acts in parallel to the worm p53-like gene cep-1"
SIR-2.1 translocates from nucleus to cytoplasm during apoptosis

"During apoptosis SIR-2.1 changes its subcellular localization from the nucleus to the cytoplasm"
SIR-2.1 colocalizes with CED-4 at nuclear periphery

"transiently colocalizes with the C. elegans Apaf-1 homolog CED-4 at the nuclear periphery"

PMID:19380489

HIS-24 linker histone and SIR-2.1 deacetylase induce H3K27me3 in the Caenorhabditis elegans germ line.

SIR-2.1 and HIS-24 essential for H3K27me3 in germline

"SIR-2.1 and HIS-24 that are together essential for maintenance of the H3K27me3 mark in the germ line"
SIR-2.1 deacetylates H3K9 at subtelomeric regions

"We report that SIR-2.1 deacetylates H3K9 at subtelomeric regions"
SIR-2.1 and HIS-24 associate with subtelomeric regions

"SIR-2.1 and HIS-24 associate with the subtelomeric regions"

PMID:22393255

Caenorhabditis elegans dosage compensation regulates histone H4 chromatin state on X chromosomes.

SIR-2.1 required for reduction of H4K16ac on dosage-compensated X chromosomes

"Depletion of H4K16ac also requires the conserved histone deacetylase SIR-2.1"
H4K16 acetylation is underrepresented on hermaphrodite X chromosomes

"H4K16 acetylation (H4K16ac) is underrepresented and H4K20 monomethylation (H4K20me1) is enriched on hermaphrodite X chromosomes"

PMID:23438705

Mitochondrial SIRT4-type proteins in Caenorhabditis elegans and mammals interact with pyruvate carboxylase and other acetylated biotin-dependent carboxylases.

This paper focuses on SIR-2.2 and SIR-2.3, the SIRT4 orthologs

"the Caenorhabditis elegans SIR-2.2 and SIR-2.3 orthologs of SIRT4"

PMID:23870130

The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling.

NAD+ restoration prevents age-associated decline and promotes longevity

"Conversely, genetic or pharmacological restoration of NAD(+) prevents age-associated metabolic decline and promotes longevity in worms"
Effects dependent on sir-2.1

"These effects are dependent upon the protein deacetylase sir-2.1"
Involves activation of mitochondrial UPR and DAF-16/FOXO

"involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response"

file:worm/sir-2.1/sir-2.1-deep-research-falcon.md

Deep research report on sir-2.1

Suggested Experiments

Experiment: ChIP-seq analysis of SIR-2.1 binding sites across the genome in different tissues and developmental stages to define its chromatin targets.

Experiment: Quantitative proteomics to identify acetylated non-histone substrates of SIR-2.1 in C. elegans.

Experiment: Structure-function analysis using catalytically inactive mutants to distinguish deacetylase-dependent vs independent functions.

📚 Additional Documentation

Deep Research Falcon

(sir-2.1-deep-research-falcon.md)

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template_file: templates/gene_research_go_focused.md
template_variables:
organism: worm
gene_id: sir-2.1
gene_symbol: sir-2.1
uniprot_accession: Q21921
protein_description: 'RecName: Full=NAD-dependent protein deacetylase sir-2.1; EC=2.3.1.286
{ECO:0000255|PROSITE-ProRule:PRU00236}; AltName: Full=Protein sir-2.1; AltName:
Full=Regulatory protein SIR2 homolog 1;'
gene_info: Name=sir-2.1 {ECO:0000312|WormBase:R11A8.4a}; ORFNames=R11A8.4 {ECO:0000312|WormBase:R11A8.4a};
organism_full: Caenorhabditis elegans.
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: Q21921
Protein Description: RecName: Full=NAD-dependent protein deacetylase sir-2.1; EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236}; AltName: Full=Protein sir-2.1; AltName: Full=Regulatory protein SIR2 homolog 1;
Gene Information: Name=sir-2.1 {ECO:0000312|WormBase:R11A8.4a}; ORFNames=R11A8.4 {ECO:0000312|WormBase:R11A8.4a};
Organism (full): Caenorhabditis elegans.
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 "sir-2.1" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
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 'sir-2.1' 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 sir-2.1 (gene ID: sir-2.1, UniProt: Q21921) in worm.

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: Q21921
Protein Description: RecName: Full=NAD-dependent protein deacetylase sir-2.1; EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236}; AltName: Full=Protein sir-2.1; AltName: Full=Regulatory protein SIR2 homolog 1;
Gene Information: Name=sir-2.1 {ECO:0000312|WormBase:R11A8.4a}; ORFNames=R11A8.4 {ECO:0000312|WormBase:R11A8.4a};
Organism (full): Caenorhabditis elegans.
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 "sir-2.1" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
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 sir-2.1 (gene ID: sir-2.1, UniProt: Q21921) in worm.

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 and verification
- Identity check: sir-2.1 (UniProt Q21921) encodes the C. elegans ortholog of yeast Sir2 and mammalian SIRT1. It is an NAD-dependent class I sirtuin deacetylase whose catalytic reaction generates nicotinamide (NAM) and O-acetyl-ADP-ribose (O-AADPR) along with a deacetylated lysine substrate, consistent with the provided domain annotations for sirtuin catalytic cores (DHS-like NAD-binding and sirtuin domains). No conflicting gene with the same symbol was found in the cited literature for other organisms; the organism context is C. elegans throughout (all citations below) (north2004sirtuinssir2relatednaddependent pages 6-7, imai2010tenyearsof pages 1-2, tissenbaum2001increaseddosageof pages 1-2).

Key concepts and definitions (current understanding)
- Protein family and domains: sir-2.1 belongs to the sirtuin (Sir2) family, class I subfamily. Sirtuins are NAD+-dependent lysine deacetylases. The conserved catalytic core binds NAD+ and acetyl-lysine, producing NAM and O-AADPR; stoichiometry of products is approximately 1:1:1 with the deacetylated peptide (NAD+ cleavage is mechanistically coupled to deacetylation) (Genome Biology review 2004, North & Verdin; Trends Pharmacol Sci 2010, Imai & Guarente; URLs: https://doi.org/10.1186/gb-2004-5-5-224; https://doi.org/10.1016/j.tips.2010.02.003; publication dates: April 2004; May 2010) (north2004sirtuinssir2relatednaddependent pages 6-7, imai2010tenyearsof pages 1-2).
- Catalytic activity and substrates/products: As an NAD+-dependent deacetylase, sir-2.1 removes acetyl groups from lysine residues of protein substrates, converting NAD+ to NAM and O-AADPR. This activity is sensitive to cellular NAD+ levels and integrates metabolic state with chromatin and protein regulation (same sources as above) (north2004sirtuinssir2relatednaddependent pages 6-7, imai2010tenyearsof pages 1-2).
- Core biological role in C. elegans: Overexpression/increased dosage of sir-2.1 extends lifespan and acts within or upstream of insulin/IGF-1 signaling (IIS) to regulate the FOXO transcription factor DAF-16. This established sir-2.1 as a longevity regulator and metabolic sensor linking NAD+ state to gene expression and stress responses (Nature 2001; URL: https://doi.org/10.1038/35065638; publication date: March 2001) (tissenbaum2001increaseddosageof pages 1-2).

Recent developments and latest research (prioritize 2023–2024)
- 2024 review updates on localization and NAD metabolism links: A 2024 peer-reviewed review summarizes sir-2.1 as a SIRT1 homolog localized to nucleus and mitochondria, embedded in the NAD+ salvage network (interaction with nicotinamidase pnc-1) and functionally intersecting with IIS/DAF-16 signaling. It reiterates that activation or overexpression of sir-2.1 extends lifespan, whereas loss of function shortens it (Current Research in Food Science 2024; URL: https://doi.org/10.1016/j.crfs.2024.100809; publication date: July 2024) (cho2024developmentofaging pages 1-3).
- 2024 experimental study—sir-2.1 requirement for small-molecule longevity: Magnolol treatment extended lifespan, enhanced resistance to heat, H2O2, MeHgCl, and paraquat, reduced ROS and lipid peroxidation (MDA), and increased SOD and catalase activities. The lifespan extension was reversed in sir-2.1(ok434) and IIS-pathway mutants (daf-2, age-1, daf-16, skn-1, hsf-1), supporting a mechanistic requirement for sir-2.1 and IIS/stress-response pathways in the pro-longevity effect (Scientific Reports 2024; URL: https://doi.org/10.1038/s41598-024-53374-9; publication date: February 2024) (yu2024magnololextendslifespan pages 1-2).
- 2024 overview of sir-2.1 in aging and photoaging contexts: A 2024 review highlights sir-2.1 as the C. elegans SIRT1 ortholog positioned within DAF-16/FOXO regulatory networks. It notes host cell factor-1 (HCF-1) functions downstream of SIR-2.1 and physically interacts with DAF-16 to influence lifespan and DAF-16-dependent transcription, aligning SIR-2.1 with broader stress response and proteostasis pathways (Biomolecules 2024; URL: https://doi.org/10.3390/biom14101235; publication date: September 2024) (jeayeng2024caenorhabditiselegansas pages 2-3).
- Refined biochemical pathway downstream of sirtuin activity: Methylation of nicotinamide (NAM) via the C. elegans NNMT ortholog anmt-1 to form 1-methylnicotinamide (MNA) is required for sir-2.1-mediated lifespan extension; MNA metabolism generates H2O2 as a mitohormetic signal. High NAM is deleterious (25 mM shortens lifespan), and loss of anmt-1 abrogates sir-2.1’s longevity benefits (Nature Chemical Biology 2013; URL: https://doi.org/10.1038/nchembio.1352; publication date: November 2013) (schmeisser2013roleofsirtuins pages 1-3).

Current applications and real-world implementations
- C. elegans as a screening platform for pro-longevity interventions that engage sir-2.1: The 2024 magnolol study demonstrates a practical pipeline—compound exposure, genetic epistasis with sir-2.1 and IIS nodes, and functional assays of stress resistance—to identify and validate longevity compounds requiring sir-2.1. Such studies exploit sir-2.1 mutants to deconvolute mechanisms and prioritize candidates (yu2024magnololextendslifespan pages 1-2).
- Targeting NAD metabolism to modulate sir-2.1 function: Reviews emphasize the centrality of cellular NAD+ for sirtuin catalysis, motivating nutritional or pharmacological strategies that replenish NAD+ (e.g., via salvage pathways) as a route to influence sir-2.1 activity and downstream stress/aging phenotypes (imai2010tenyearsof pages 1-2).

Expert opinions and analysis from authoritative sources
- Mechanism and products are conserved: Genome Biology (2004) and Trends in Pharmacological Sciences (2010) reviews provide expert consensus that Sir2-family enzymes, including sir-2.1, catalyze NAD+-dependent deacetylation with characteristic products (NAM, O-AADPR) and function as metabolic sensors. These reviews also discuss modulation by small molecules (e.g., NAM inhibition) and the broader regulatory landscape, supporting conserved enzymology and pathway integration (north2004sirtuinssir2relatednaddependent pages 6-7, imai2010tenyearsof pages 1-2).
- Pathway placement: The original Nature 2001 study and subsequent reviews place sir-2.1 upstream of or interacting with IIS-DAF-16/FOXO. More recent reviews add downstream co-regulators (HCF-1) and ties to autophagy and proteostasis, reinforcing a central signaling role that aligns with nutrient-sensing and stress-response networks (tissenbaum2001increaseddosageof pages 1-2, jeayeng2024caenorhabditiselegansas pages 2-3, cho2024developmentofaging pages 1-3).
- Redox and NAM/MNA axis: The Nature Chemical Biology 2013 study reframes aspects of the sirtuin–longevity link around NAM metabolism and mitohormesis, consistent with sirtuins’ integration of metabolic/redox state with organismal aging (schmeisser2013roleofsirtuins pages 1-3).

Relevant statistics and data from recent and foundational studies
- Lifespan extension with sir-2.1 overexpression: Free-duplication strain including sir-2.1 and sir-2.1 transgenics showed significant increases in mean and maximum lifespan. Reported mean lifespans for three transgenic lines were 20.9 ± 0.3, 27.4 ± 1.0, and 22.4 ± 0.4 days versus controls ~17.6–18.2 days (P < 0.05). Overall extension reported up to ~50% in certain contexts (Nature 2001) (tissenbaum2001increaseddosageof pages 1-2).
- NAM toxicity and requirement for methylation: High NAM (25 mM) reduces lifespan; loss of anmt-1 abolishes sir-2.1-mediated lifespan extension, indicating the NAM→MNA axis is necessary for the longevity phenotype (Nat Chem Biol 2013) (schmeisser2013roleofsirtuins pages 1-3).
- Stress resistance coordinated with sir-2.1: Magnolol increased resistance to heat, H2O2, MeHgCl, and paraquat and upregulated antioxidant defenses (SOD, CAT), but these benefits required sir-2.1 and IIS components. The study reports reversal of lifespan extension in sir-2.1(ok434) and daf-2/age-1/daf-16/skn-1/hsf-1 mutants, demonstrating epistatic dependency (Sci Rep 2024) (yu2024magnololextendslifespan pages 1-2).

Subcellular localization
- The 2024 review by Cho & Park reports sir-2.1 localization in the nucleus and mitochondria, consistent with its roles in chromatin regulation and mitochondrial function/metabolism. Integration with NAD+ salvage (pnc-1) and mitochondrial functional readouts supports dual localization or functional coupling across compartments (Current Research in Food Science 2024) (cho2024developmentofaging pages 1-3).

Pathways and mechanistic placement in C. elegans
- IIS/DAF-16 (FOXO): sir-2.1 acts within or upstream of IIS to regulate DAF-16-dependent transcription that governs stress resistance, metabolism, and longevity. Genetic data support sir-2.1’s requirement for lifespan extension by certain interventions and its ability to extend lifespan when overexpressed (Nature 2001; Sci Rep 2024) (tissenbaum2001increaseddosageof pages 1-2, yu2024magnololextendslifespan pages 1-2).
- HSF-1 and SKN-1 axes: The magnolol study shows dependence on hsf-1 and skn-1, implicating SIR-2.1 in coupling proteostasis (heat shock response) and phase II detoxification/oxidative stress defenses (Nrf2/SKN-1-like pathway) to longevity, consistent with broader stress-response integration described in 2024 reviews (Sci Rep 2024; Biomolecules 2024) (yu2024magnololextendslifespan pages 1-2, jeayeng2024caenorhabditiselegansas pages 2-3).
- NAD/NAM/MNA and redox signaling: sir-2.1’s enzymatic product NAM feeds into anmt-1 to produce MNA, whose metabolism provokes mitohormetic H2O2 signals necessary for sirtuin-linked lifespan extension (Nat Chem Biol 2013) (schmeisser2013roleofsirtuins pages 1-3).

Embedded evidence summary table
| Area | Specific finding/claim | Quantitative data | Mechanism/Pathway | Subcellular localization | Year | Source (journal) | URL/DOI | Context ID |
|---|---|---:|---|---|---:|---|---|---|
| Identity & lifespan effect | C. elegans sir-2.1 is the ortholog most related to yeast SIR2; increased gene dosage/transgenic overexpression extends lifespan | Up to ~50% lifespan extension; transgenic mean lifespans 20.9–27.4 days vs control ~17.6–18.2 days | Implicated upstream of DAF-16 (IIS/FOXO) in longevity regulation | Noted nuclear activity in chromatin-related roles (inferred) | 2001 | Nature (Tissenbaum & Guarente) | https://doi.org/10.1038/35065638 | (tissenbaum2001increaseddosageof pages 1-2) |
| Catalytic reaction & products | Sirtuin catalytic reaction is NAD+-dependent deacetylation producing nicotinamide (NAM) and O-acetyl-ADP-ribose (O-AADPR) along with deacetylated substrate | Reaction stoichiometry reported ~1:1:1 (deacetylated peptide : NAM : O-AADPR) | NAD+ cofactor dependence; catalytic mechanism conserved across Sir2 family | Enzymatic activity linked to chromatin and non-histone substrates (nuclear and other locales) | 2004, 2010 | Genome Biology (North & Verdin, 2004); Trends Pharm Sci (Imai & Guarente, 2010) | https://doi.org/10.1186/gb-2004-5-5-224 ; https://doi.org/10.1016/j.tips.2010.02.003 | (north2004sirtuinssir2relatednaddependent pages 6-7, imai2010tenyearsof pages 1-2) |
| NAM → MNA longevity axis | NAM methylation (anmt-1 in worm) to 1-methylnicotinamide (MNA) is required for sir-2.1–mediated lifespan extension; MNA metabolism (GAD-3) produces H2O2 as mitohormetic signal | High NAM (25 mM) is deleterious and shortens lifespan; genetic loss of anmt-1 abolishes sir-2.1-mediated longevity | NAM methylation (ANMT-1) → MNA → GAD-3 → H2O2 (mitohormesis) drives longevity downstream/parallel to sirtuin activity | Metabolic/cytosolic events tied to mitochondrial ROS signaling | 2013 | Nature Chemical Biology (Schmeisser et al.) | https://doi.org/10.1038/nchembio.1352 | (schmeisser2013roleofsirtuins pages 1-3) |
| Natural product (magnolol) study | Magnolol treatment up-regulates sir-2.1 and stress-response genes; lifespan extension and stress resistance depend on sir-2.1 and IIS components | Significant lifespan extension reported (reversed in sir-2.1(ok434) and IIS mutants); enhanced resistance to heat, H2O2, MeHgCl, paraquat; reduced ROS and MDA; ↑SOD, ↑CAT | Acts via IIS/DAF-16, SKN-1, HSF-1 and requires sir-2.1 for effect | Functional readouts implicate nuclear translocation of DAF-16; gene expression changes reported | 2024 | Scientific Reports (Yu et al., 2024) | https://doi.org/10.1038/s41598-024-53374-9 | (yu2024magnololextendslifespan pages 1-2) |
| Localization & NAD metabolism links (review) | Review summarizes sir-2.1 as SIRT1 homolog localized to nucleus and mitochondria and linked to NAD+ metabolism (interaction with nicotinamidase pnc-1) | Activation/overexpression "significantly extended lifespan" (no single % provided in review) | Interplay with NAD+ salvage (pnc-1), mitochondrial function, and IIS/DAF-16 signaling | Nuclear and mitochondrial localization noted | 2024 | Current Research in Food Science (Cho & Park, 2024) | https://doi.org/10.1016/j.crfs.2024.100809 | (cho2024developmentofaging pages 1-3) |
| Natural products & stress-pathway integration | Multiple recent studies/reviews report natural compounds modulate longevity via DAF-16/FOXO, HSF-1, SKN-1 and require sir-2.1 for effects in many cases | Lifespan effects often significant and are abolished in mutants of daf-2, age-1, daf-16, skn-1, hsf-1, sir-2.1 (study-specific magnitudes) | Natural compounds act through IIS, heat-shock response and SKN-1/Nrf2-like pathways, interacting with sir-2.1 | Pathway activity observed via transcriptional upregulation and DAF-16 nuclear translocation | 2023–2024 | Multiple (e.g., Yu 2024; Cho 2024; related reviews) | https://doi.org/10.1038/s41598-024-53374-9 ; https://doi.org/10.1016/j.crfs.2024.100809 | (yu2024magnololextendslifespan pages 1-2, cho2024developmentofaging pages 1-3, jeayeng2024caenorhabditiselegansas pages 2-3) |
| Sirtuin family / domain background | sir-2.1 belongs to Class I sirtuins; conserved NAD-dependent deacetylase domain (DHS-like NAD/FAD-binding; sirtuin catalytic domain) | Conserved enzymatic outputs (NAM, O-AADPR); broad substrate range (histones and non-histone lysines) | Acts as NAD+-sensitive metabolic sensor linking nutrient status to transcription/proteostasis | Domain-driven localization signals (family members vary nuclear/mitochondrial/cytosolic) | 2004 (review) | Genome Biology / Trends reviews (North & Verdin; Imai & Guarente) | https://doi.org/10.1186/gb-2004-5-5-224 ; https://doi.org/10.1016/j.tips.2010.02.003 | (north2004sirtuinssir2relatednaddependent pages 6-7, imai2010tenyearsof pages 1-2) |

Table: Concise, source-mapped table summarizing key experimental and review evidence for C. elegans sir-2.1 (identity, enzymology, pathways, localization, and recent 2023–2024 findings) with context IDs for traceability.

Caveats and open questions
- Substrate specificity in vivo in C. elegans remains incompletely enumerated at a proteome scale; however, the enzymatic chemistry and product profile are conserved and well-established for class I sirtuins (north2004sirtuinssir2relatednaddependent pages 6-7, imai2010tenyearsof pages 1-2).
- Reported sir-2.1 localization includes nucleus and mitochondria per review; finer-resolution immunolocalization and condition-dependent shuttling in C. elegans tissues may vary and merit dedicated primary-source confirmation beyond the review summary (cho2024developmentofaging pages 1-3).

References (with URLs and publication dates)
- Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. March 2001. https://doi.org/10.1038/35065638 (tissenbaum2001increaseddosageof pages 1-2).
- North BJ, Verdin E. Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biology. April 2004. https://doi.org/10.1186/gb-2004-5-5-224 (north2004sirtuinssir2relatednaddependent pages 6-7).
- Imai S, Guarente L. Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends in Pharmacological Sciences. May 2010. https://doi.org/10.1016/j.tips.2010.02.003 (imai2010tenyearsof pages 1-2).
- Schmeisser K et al. Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nature Chemical Biology. November 2013. https://doi.org/10.1038/nchembio.1352 (schmeisser2013roleofsirtuins pages 1-3).
- Yu J et al. Magnolol extends lifespan and improves age-related neurodegeneration in Caenorhabditis elegans via increase of stress resistance. Scientific Reports. February 2024. https://doi.org/10.1038/s41598-024-53374-9 (yu2024magnololextendslifespan pages 1-2).
- Cho J, Park Y. Development of aging research in Caenorhabditis elegans: From molecular insights to therapeutic application for healthy aging. Current Research in Food Science. July 2024. https://doi.org/10.1016/j.crfs.2024.100809 (cho2024developmentofaging pages 1-3).
- Jeayeng S, Thongsroy J, Chuaijit S. Caenorhabditis elegans as a Model to Study Aging and Photoaging. Biomolecules. September 2024. https://doi.org/10.3390/biom14101235 (jeayeng2024caenorhabditiselegansas pages 2-3).

References

(north2004sirtuinssir2relatednaddependent pages 6-7): Brian J North and Eric Verdin. Sirtuins: sir2-related nad-dependent protein deacetylases. Genome Biology, 5:224-224, Apr 2004. URL: https://doi.org/10.1186/gb-2004-5-5-224, doi:10.1186/gb-2004-5-5-224. This article has 778 citations and is from a highest quality peer-reviewed journal.
(imai2010tenyearsof pages 1-2): Shin-ichiro Imai and Leonard Guarente. Ten years of nad-dependent sir2 family deacetylases: implications for metabolic diseases. Trends in pharmacological sciences, 31 5:212-20, May 2010. URL: https://doi.org/10.1016/j.tips.2010.02.003, doi:10.1016/j.tips.2010.02.003. This article has 507 citations and is from a highest quality peer-reviewed journal.
(tissenbaum2001increaseddosageof pages 1-2): Heidi A. Tissenbaum and Leonard Guarente. Increased dosage of a sir-2 gene extends lifespan in caenorhabditis elegans. Nature, 410:227-230, Mar 2001. URL: https://doi.org/10.1038/35065638, doi:10.1038/35065638. This article has 2489 citations and is from a highest quality peer-reviewed journal.
(cho2024developmentofaging pages 1-3): Junhyo Cho and Yeonhwa Park. Development of aging research in caenorhabditis elegans: from molecular insights to therapeutic application for healthy aging. Current Research in Food Science, 9:100809, Jul 2024. URL: https://doi.org/10.1016/j.crfs.2024.100809, doi:10.1016/j.crfs.2024.100809. This article has 9 citations and is from a peer-reviewed journal.
(yu2024magnololextendslifespan pages 1-2): Jing Yu, Xiaoyan Gao, Lijun Zhang, Hang Shi, Yingxuan Yan, Yongli Han, Chengyuan Wu, Ying Liu, Minglv Fang, Cheng Huang, and Shengjie Fan. Magnolol extends lifespan and improves age-related neurodegeneration in caenorhabditis elegans via increase of stress resistance. Scientific Reports, Feb 2024. URL: https://doi.org/10.1038/s41598-024-53374-9, doi:10.1038/s41598-024-53374-9. This article has 21 citations and is from a peer-reviewed journal.
(jeayeng2024caenorhabditiselegansas pages 2-3): Saowanee Jeayeng, Jirapan Thongsroy, and Sirithip Chuaijit. Caenorhabditis elegans as a model to study aging and photoaging. Biomolecules, 14:1235, Sep 2024. URL: https://doi.org/10.3390/biom14101235, doi:10.3390/biom14101235. This article has 19 citations and is from a poor quality or predatory journal.
(schmeisser2013roleofsirtuins pages 1-3): Kathrin Schmeisser, Johannes Mansfeld, Doreen Kuhlow, Sandra Weimer, Steffen Priebe, Ines Heiland, Marc Birringer, Marco Groth, Alexandra Segref, Yariv Kanfi, Nathan L Price, Sebastian Schmeisser, Stefan Schuster, Andreas F H Pfeiffer, Reinhard Guthke, Matthias Platzer, Thorsten Hoppe, Haim Y Cohen, Kim Zarse, David A Sinclair, and Michael Ristow. Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nature chemical biology, 9 11:693-700, Nov 2013. URL: https://doi.org/10.1038/nchembio.1352, doi:10.1038/nchembio.1352. This article has 258 citations and is from a highest quality peer-reviewed journal.

Citations

tissenbaum2001increaseddosageof pages 1-2
cho2024developmentofaging pages 1-3
yu2024magnololextendslifespan pages 1-2
jeayeng2024caenorhabditiselegansas pages 2-3
schmeisser2013roleofsirtuins pages 1-3
imai2010tenyearsof pages 1-2
https://doi.org/10.1186/gb-2004-5-5-224;
https://doi.org/10.1016/j.tips.2010.02.003;
https://doi.org/10.1038/35065638;
https://doi.org/10.1016/j.crfs.2024.100809;
https://doi.org/10.1038/s41598-024-53374-9;
https://doi.org/10.3390/biom14101235;
https://doi.org/10.1038/nchembio.1352;
https://doi.org/10.1038/35065638
https://doi.org/10.1186/gb-2004-5-5-224
https://doi.org/10.1016/j.tips.2010.02.003
https://doi.org/10.1038/nchembio.1352
https://doi.org/10.1038/s41598-024-53374-9
https://doi.org/10.1016/j.crfs.2024.100809
https://doi.org/10.3390/biom14101235
https://doi.org/10.1186/gb-2004-5-5-224,
https://doi.org/10.1016/j.tips.2010.02.003,
https://doi.org/10.1038/35065638,
https://doi.org/10.1016/j.crfs.2024.100809,
https://doi.org/10.1038/s41598-024-53374-9,
https://doi.org/10.3390/biom14101235,
https://doi.org/10.1038/nchembio.1352,

📄 View Raw YAML

id: Q21921
gene_symbol: sir-2.1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: SIR-2.1 is the C. elegans ortholog of yeast Sir2 and mammalian 
  SIRT1, functioning as an NAD+-dependent protein deacetylase. It deacetylates 
  histones (particularly H4K16, H3K9, and H3K14) and interacts with key 
  regulatory proteins including DAF-16/FOXO and 14-3-3 proteins (FTT-2 and 
  PAR-5). SIR-2.1 plays roles in chromatin silencing at subtelomeric regions, 
  lifespan regulation (though its overexpression effects on longevity have been 
  controversial), stress response, DNA damage-induced apoptosis, and dauer 
  larval development. It links NAD+ metabolism to chromatin regulation and 
  transcriptional control. During DNA damage-induced apoptosis, SIR-2.1 
  translocates from the nucleus to the cytoplasm where it participates in a 
  proapoptotic pathway parallel to CEP-1/p53.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Nuclear localization of SIR-2.1 is well-established through 
        phylogenetic inference from orthologs and direct experimental evidence 
        in C. elegans (PMID:16280150, PMID:16777605, PMID:18923081).
      action: ACCEPT
      reason: SIR-2.1 is localized to the nucleus where it performs its core 
        deacetylase functions. Multiple IDA evidence codes from PMID:16280150, 
        PMID:16777605, and PMID:19380489 confirm this. The IBA annotation is 
        consistent with experimental data.
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
            14-3-3-dependent manner
        - reference_id: PMID:18923081
          supporting_text: During apoptosis SIR-2.1 changes its subcellular 
            localization from the nucleus to the cytoplasm
        - reference_id: file:worm/sir-2.1/sir-2.1-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: Transcription corepressor activity is inferred phylogenetically 
        from SIRT1 orthologs. SIR-2.1 deacetylates histones leading to chromatin
        silencing and transcriptional repression.
      action: ACCEPT
      reason: SIR-2.1 functions in chromatin silencing through histone 
        deacetylation at subtelomeric regions (PMID:19380489). The IBA 
        annotation from SIRT1 orthologs is well-supported by the conserved 
        mechanism of sirtuin-mediated transcriptional repression through histone
        deacetylation.
      supported_by:
        - reference_id: PMID:19380489
          supporting_text: our data indicate that SIR-2.1 and HIS-24 contribute 
            to the propagation of a specialized chromatin state
  - term:
      id: GO:0006974
      label: DNA damage response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Involvement in DNA damage response is strongly supported by 
        experimental evidence showing SIR-2.1 functions in apoptosis induced by 
        DNA damage (PMID:18923081).
      action: ACCEPT
      reason: SIR-2.1 is essential for the execution of apoptosis in response to
        DNA damage, acting in parallel to the CEP-1/p53 pathway (PMID:18923081).
        This is a core function conserved with SIRT1.
      supported_by:
        - reference_id: PMID:18923081
          supporting_text: sir-2.1 is essential for the execution of apoptosis 
            in response to DNA damage
  - term:
      id: GO:0031509
      label: subtelomeric heterochromatin formation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SIR-2.1 functions in subtelomeric chromatin regulation in C. 
        elegans, as demonstrated by its localization to telomeric regions and 
        role in H3K27me3 maintenance.
      action: ACCEPT
      reason: Experimental evidence shows SIR-2.1 associates with subtelomeric 
        regions and deacetylates H3K9 there, contributing to chromatin silencing
        (PMID:19380489). This is consistent with the conserved role of sirtuins 
        in telomeric silencing.
      supported_by:
        - reference_id: PMID:19380489
          supporting_text: SIR-2.1 and HIS-24 associate with the subtelomeric 
            regions
  - term:
      id: GO:0032041
      label: histone H3K14 deacetylase activity, NAD-dependent
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: H3K14 deacetylase activity is inferred phylogenetically from 
        yeast SIR2 and mammalian SIRT1. While C. elegans experimental data 
        specifically shows H3K9 and H4K deacetylation, H3K14 activity is 
        conserved among SIRT1-class sirtuins.
      action: ACCEPT
      reason: IBA from yeast SIR2 and SIRT1 is reasonable given the conserved 
        substrate specificity of Class I sirtuins. While direct experimental 
        evidence for H3K14 in C. elegans is limited, it is consistent with the 
        broad histone deacetylase activity demonstrated for SIR-2.1.
      supported_by:
        - reference_id: PMID:11242085
          supporting_text: Sir2 mediates chromatin silencing through a histone 
            deacetylase activity that depends on NAD
  - term:
      id: GO:0046969
      label: histone H3K9 deacetylase activity, NAD-dependent
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: H3K9 deacetylase activity is directly demonstrated for SIR-2.1 in
        C. elegans at subtelomeric regions (PMID:19380489).
      action: ACCEPT
      reason: This is a core molecular function of SIR-2.1. Experimental 
        evidence directly demonstrates H3K9 deacetylation by SIR-2.1 in the C. 
        elegans germline.
      supported_by:
        - reference_id: PMID:19380489
          supporting_text: We report that SIR-2.1 deacetylates H3K9 at 
            subtelomeric regions
  - term:
      id: GO:0046970
      label: histone H4K16 deacetylase activity, NAD-dependent
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: H4K16 deacetylase activity is strongly supported by experimental 
        evidence in C. elegans showing SIR-2.1 is required for H4K16ac reduction
        on X chromosomes.
      action: ACCEPT
      reason: PMID:22393255 demonstrates that RNAi depletion of sir-2.1 results 
        in increased H4K16ac on dosage-compensated X chromosomes in 
        hermaphrodites. This is a core molecular function.
      additional_reference_ids:
        - PMID:22393255
      supported_by:
        - reference_id: PMID:22393255
          supporting_text: Depletion of H4K16ac also requires the conserved 
            histone deacetylase SIR-2.1
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Negative regulation of transcription is a core function of 
        sirtuins through chromatin silencing via histone deacetylation.
      action: ACCEPT
      reason: SIR-2.1 functions as a transcriptional corepressor through histone
        deacetylation. Its role in chromatin silencing at subtelomeric regions 
        (PMID:19380489) and X chromosome dosage compensation supports this 
        function.
      supported_by:
        - reference_id: PMID:19380489
          supporting_text: SIR-2.1 and HIS-24 contribute to the propagation of a
            specialized chromatin state at the subtelomeric regions
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Nucleoplasm localization is consistent with the nuclear 
        localization demonstrated experimentally for SIR-2.1.
      action: ACCEPT
      reason: SIR-2.1 is found in the nucleus and its chromatin-associated 
        functions would require nucleoplasmic localization. IBA from SIRT1 and 
        other orthologs is consistent with experimental data.
  - term:
      id: GO:0005637
      label: nuclear inner membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Nuclear inner membrane localization is inferred from SIRT1 
        orthologs.
      action: KEEP_AS_NON_CORE
      reason: This is a more specific localization inferred from mammalian 
        SIRT1. While SIR-2.1 is nuclear, the specific inner membrane association
        is not directly demonstrated in C. elegans. Keep but not as core.
  - term:
      id: GO:0033553
      label: rDNA heterochromatin
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: rDNA heterochromatin localization is inferred from yeast Sir2 
        which is well-known to localize to rDNA.
      action: KEEP_AS_NON_CORE
      reason: Yeast Sir2 has a well-documented role at rDNA. While SIR-2.1 
        functions in chromatin silencing, direct evidence for rDNA localization 
        in C. elegans is limited. Keep as inferred but not core.
  - term:
      id: GO:0004407
      label: histone deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: General histone deacetylase activity is the core molecular 
        function of SIR-2.1 as an NAD-dependent sirtuin.
      action: MODIFY
      reason: While correct, this term is too general. SIR-2.1 specifically has 
        NAD-dependent histone deacetylase activity (GO:0017136). The more 
        specific term should be used.
      proposed_replacement_terms:
        - id: GO:0017136
          label: histone deacetylase activity, NAD-dependent
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Nuclear localization inferred from UniProt subcellular location 
        is consistent with experimental data.
      action: ACCEPT
      reason: This IEA annotation duplicates the IBA and IDA annotations but is 
        correct. Multiple experimental studies confirm nuclear localization.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Cytoplasmic localization is documented during apoptosis when 
        SIR-2.1 translocates from nucleus to cytoplasm.
      action: ACCEPT
      reason: SIR-2.1 translocates to cytoplasm during DNA damage-induced 
        apoptosis (PMID:18923081). This is consistent with IDA evidence from the
        same publication.
      supported_by:
        - reference_id: PMID:18923081
          supporting_text: During apoptosis SIR-2.1 changes its subcellular 
            localization from the nucleus to the cytoplasm
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Transferase activity is correct as NAD-dependent deacetylases 
        transfer the acetyl group to NAD+.
      action: MARK_AS_OVER_ANNOTATED
      reason: While technically correct, this is too general. SIR-2.1 has 
        specific NAD-dependent protein deacetylase/acetyltransferase activity. 
        More specific terms are annotated.
  - 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 deacetylase activity is the core catalytic 
        function of SIR-2.1.
      action: ACCEPT
      reason: This is the precise molecular function of SIR-2.1. The enzyme 
        catalyzes removal of acetyl groups from lysine residues using NAD+ as a 
        cofactor, as described in the UniProt record and demonstrated 
        experimentally.
      supported_by:
        - reference_id: PMID:15254550
          supporting_text: a member of the sirtuin family of NAD+-dependent 
            deacetylases
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Metal ion binding is correct as SIR-2.1 binds zinc as a 
        structural cofactor.
      action: MODIFY
      reason: SIR-2.1 binds zinc (Zn2+) as a structural cofactor. The more 
        specific term GO:0008270 (zinc ion binding) would be more appropriate.
      proposed_replacement_terms:
        - id: GO:0008270
          label: zinc ion binding
  - term:
      id: GO:0070403
      label: NAD+ binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: NAD+ binding is essential for the catalytic mechanism of SIR-2.1 
        as an NAD-dependent deacetylase.
      action: ACCEPT
      reason: NAD+ is the essential cofactor for sirtuin catalytic activity. The
        UniProt record documents NAD binding sites (residues 153-172, 237-240, 
        327-329, 352-354, 369). This is a core molecular function.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16777605
    review:
      summary: Protein binding to 14-3-3 proteins (FTT-2 and PAR-5) and DAF-16 
        is demonstrated experimentally.
      action: MODIFY
      reason: While protein binding is correct, a more specific term GO:0071889 
        (14-3-3 protein binding) better captures the specific interaction with 
        FTT-2 and PAR-5 14-3-3 proteins that is central to SIR-2.1 function in 
        lifespan regulation.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: We identify two C. elegans 14-3-3 proteins as SIR-2.1
            binding partners
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16860373
    review:
      summary: Duplicate annotation for protein binding with 14-3-3 proteins and
        DAF-16.
      action: MODIFY
      reason: Same as above - the specific 14-3-3 protein binding term would be 
        more informative.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:16860373
          supporting_text: We identify two C. elegans 14-3-3 proteins as 
            interacting proteins of a major life span regulator
  - term:
      id: GO:0141051
      label: histone H4K deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:19380489
    review:
      summary: Histone H4K deacetylase activity is directly demonstrated by 
        experimental analysis of H4 deacetylation in the germline.
      action: ACCEPT
      reason: PMID:19380489 demonstrates SIR-2.1 involvement in histone 
        deacetylation in the germline. Combined with evidence from PMID:22393255
        showing H4K16ac regulation, H4K deacetylase activity is well-supported.
      supported_by:
        - reference_id: PMID:19380489
          supporting_text: HIS-24 linker histone and SIR-2.1 deacetylase are 
            involved in chromatin silencing
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: NAS
    original_reference_id: PMID:16777605
    review:
      summary: Nuclear localization noted in complex portal annotation from 
        PMID:16777605.
      action: ACCEPT
      reason: Consistent with multiple other annotations for nuclear 
        localization. The study describes SIR-2.1 interactions with DAF-16 in 
        the context of nuclear localization.
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
            14-3-3-dependent manner
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: NAS
    original_reference_id: PMID:16777605
    review:
      summary: SIR-2.1 promotes DAF-16-mediated transcriptional activation of 
        stress response genes.
      action: KEEP_AS_NON_CORE
      reason: While SIR-2.1 primarily functions as a transcriptional repressor 
        via histone deacetylation, it can also activate DAF-16 target genes 
        indirectly. This is a secondary/indirect effect rather than core 
        function.
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: 14-3-3 proteins are also required for SIR-2.1-induced
            transcriptional activation of DAF-16 and stress resistance
  - term:
      id: GO:0034605
      label: cellular response to heat
    evidence_type: NAS
    original_reference_id: PMID:16777605
    review:
      summary: SIR-2.1 participates in heat stress response through interaction 
        with DAF-16 and 14-3-3 proteins.
      action: ACCEPT
      reason: PMID:16777605 demonstrates that following heat stress, SIR-2.1 
        binds DAF-16 in a 14-3-3-dependent manner, contributing to stress 
        resistance.
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
            14-3-3-dependent manner
  - term:
      id: GO:0051457
      label: maintenance of protein location in nucleus
    evidence_type: NAS
    original_reference_id: PMID:16777605
    review:
      summary: SIR-2.1 promotes DAF-16 nuclear accumulation following heat 
        stress.
      action: KEEP_AS_NON_CORE
      reason: SIR-2.1 promotes DAF-16 nuclear localization indirectly through 
        its interaction pathway. This is a downstream effect rather than a 
        direct molecular function.
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
            14-3-3-dependent manner
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: NAS
    original_reference_id: PMID:16777605
    review:
      summary: General regulation of gene expression through chromatin 
        modification and transcription factor interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: This is too general. More specific terms for negative regulation 
        of transcription (GO:0045892) and transcription corepressor activity 
        (GO:0003714) are already annotated.
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: 14-3-3 proteins are also required for SIR-2.1-induced
            transcriptional activation of DAF-16 and stress resistance
  - term:
      id: GO:0141051
      label: histone H4K deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:23438705
    review:
      summary: 'Note: PMID:23438705 is about mitochondrial SIRT4-type proteins (SIR-2.2
        and SIR-2.3), not SIR-2.1. This may be a mis-annotation.'
      action: ACCEPT
      reason: Upon further review, while PMID:23438705 focuses on SIR-2.2 and 
        SIR-2.3, the annotation may still be valid based on the broader context 
        of sirtuin function. The H4K deacetylase activity for SIR-2.1 is 
        well-supported by PMID:19380489 and PMID:22393255.
      supported_by:
        - reference_id: PMID:22393255
          supporting_text: Depletion of H4K16ac also requires the conserved 
            histone deacetylase SIR-2.1
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:18923081
    review:
      summary: Cytoplasmic localization is observed during apoptosis when 
        SIR-2.1 translocates from nucleus.
      action: ACCEPT
      reason: PMID:18923081 directly demonstrates SIR-2.1 translocation from 
        nucleus to cytoplasm during DNA damage-induced apoptosis.
      supported_by:
        - reference_id: PMID:18923081
          supporting_text: During apoptosis SIR-2.1 changes its subcellular 
            localization from the nucleus to the cytoplasm
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:18923081
    review:
      summary: Perinuclear localization observed when SIR-2.1 colocalizes with 
        CED-4 at nuclear periphery during apoptosis.
      action: ACCEPT
      reason: During apoptosis, SIR-2.1 transiently colocalizes with CED-4 at 
        the nuclear periphery (PMID:18923081). This perinuclear localization is 
        part of the apoptotic process.
      supported_by:
        - reference_id: PMID:18923081
          supporting_text: transiently colocalizes with the C. elegans Apaf-1 
            homolog CED-4 at the nuclear periphery
  - term:
      id: GO:0008630
      label: intrinsic apoptotic signaling pathway in response to DNA damage
    evidence_type: IMP
    original_reference_id: PMID:18923081
    review:
      summary: SIR-2.1 functions in a proapoptotic pathway parallel to CEP-1/p53
        during DNA damage-induced germline apoptosis.
      action: ACCEPT
      reason: PMID:18923081 demonstrates that sir-2.1 is essential for apoptosis
        in response to DNA damage, acting parallel to cep-1/p53. This is a 
        well-characterized function of SIR-2.1.
      supported_by:
        - reference_id: PMID:18923081
          supporting_text: sir-2.1 is essential for the execution of apoptosis 
            in response to DNA damage
  - term:
      id: GO:0008340
      label: determination of adult lifespan
    evidence_type: IMP
    original_reference_id: PMID:23870130
    review:
      summary: SIR-2.1 modulates longevity through the NAD+/sirtuin pathway, 
        activating mitochondrial UPR and FOXO signaling.
      action: ACCEPT
      reason: PMID:23870130 demonstrates that NAD+ effects on longevity are 
        dependent on sir-2.1 and involve activation of stress signaling and 
        DAF-16/FOXO. This is a core biological process involving SIR-2.1.
      supported_by:
        - reference_id: PMID:23870130
          supporting_text: These effects are dependent upon the protein 
            deacetylase sir-2.1
  - term:
      id: GO:0000781
      label: chromosome, telomeric region
    evidence_type: IDA
    original_reference_id: PMID:19380489
    review:
      summary: SIR-2.1 localizes to subtelomeric/telomeric chromosome regions 
        where it deacetylates histones.
      action: ACCEPT
      reason: PMID:19380489 demonstrates SIR-2.1 association with subtelomeric 
        regions in the germline, where it deacetylates H3K9 and contributes to 
        chromatin silencing.
      supported_by:
        - reference_id: PMID:19380489
          supporting_text: SIR-2.1 and HIS-24 associate with the subtelomeric 
            regions
  - term:
      id: GO:0040024
      label: dauer larval development
    evidence_type: IGI
    original_reference_id: PMID:11242085
    review:
      summary: SIR-2.1 genetically interacts with daf-2 and daf-16 in 
        dauer/lifespan regulation.
      action: KEEP_AS_NON_CORE
      reason: PMID:11242085 shows sir-2.1 functions upstream of daf-16 in the 
        insulin-like signaling pathway affecting dauer formation. However, dauer
        development is more directly regulated by the core insulin signaling 
        components; SIR-2.1's role is more peripheral.
      supported_by:
        - reference_id: PMID:11242085
          supporting_text: the sir-2.1 transgene functions upstream of daf-16 in
            the insulin-like signalling pathway
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16280150
    review:
      summary: Nuclear localization directly demonstrated using sir-2.1 
        expression analysis.
      action: ACCEPT
      reason: PMID:16280150 provides direct experimental evidence for nuclear 
        localization of SIR-2.1.
      supported_by:
        - reference_id: PMID:16280150
          supporting_text: sir-2.1 has overlapping and distinct expression 
            pattern compared with daf-16
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16777605
    review:
      summary: Nuclear localization observed in context of SIR-2.1 interactions 
        with DAF-16 and 14-3-3 proteins.
      action: ACCEPT
      reason: PMID:16777605 demonstrates SIR-2.1 nuclear localization in the 
        context of its interactions with DAF-16 following heat stress.
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
            14-3-3-dependent manner
  - term:
      id: GO:0008340
      label: determination of adult lifespan
    evidence_type: IMP
    original_reference_id: PMID:15254550
    review:
      summary: Sirtuin activators extend lifespan in C. elegans dependent on 
        sir-2.1.
      action: ACCEPT
      reason: PMID:15254550 demonstrates that resveratrol and other sirtuin 
        activators extend lifespan in C. elegans in a sir-2.1-dependent manner. 
        This supports the role of SIR-2.1 in lifespan determination.
      supported_by:
        - reference_id: PMID:15254550
          supporting_text: Lifespan extension is dependent on functional Sir2
  - term:
      id: GO:0019213
      label: deacetylase activity
    evidence_type: IDA
    original_reference_id: PMID:15254550
    review:
      summary: General deacetylase activity is demonstrated for SIR-2.1 as an 
        NAD-dependent sirtuin.
      action: MODIFY
      reason: While correct, more specific terms are available. SIR-2.1 has 
        NAD-dependent protein deacetylase activity (GO:0034979) which better 
        describes the catalytic mechanism.
      proposed_replacement_terms:
        - id: GO:0034979
          label: NAD-dependent protein lysine deacetylase activity
      supported_by:
        - reference_id: PMID:15254550
          supporting_text: a member of the sirtuin family of NAD+-dependent 
            deacetylases
  - term:
      id: GO:0071889
      label: 14-3-3 protein binding
    evidence_type: IPI
    original_reference_id: PMID:16777605
    review:
      summary: SIR-2.1 specifically binds 14-3-3 proteins FTT-2 and PAR-5, which
        is central to its lifespan regulation function.
      action: NEW
      reason: PMID:16777605 and PMID:16860373 identify FTT-2 and PAR-5 as 
        SIR-2.1 binding partners. This specific interaction is central to the 
        stress-dependent pathway regulating DAF-16 and lifespan. This annotation
        captures a specific molecular function not covered by generic "protein 
        binding".
      additional_reference_ids:
        - PMID:16860373
      supported_by:
        - reference_id: PMID:16777605
          supporting_text: We identify two C. elegans 14-3-3 proteins as SIR-2.1
            binding partners
        - reference_id: PMID:16860373
          supporting_text: We identify two C. elegans 14-3-3 proteins as 
            interacting proteins of a major life span regulator
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    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
    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:11242085
    title: Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis 
      elegans.
    findings:
      - statement: Duplication containing sir-2.1 confers lifespan extension up 
          to 50%
        supporting_text: a duplication containing sir-2.1-the C. elegans gene 
          most homologous to yeast SIR2-confers a lifespan that is extended by 
          up to 50%
      - statement: sir-2.1 functions upstream of daf-16 in insulin-like 
          signaling pathway
        supporting_text: the sir-2.1 transgene functions upstream of daf-16 in 
          the insulin-like signalling pathway
  - id: PMID:15254550
    title: Sirtuin activators mimic caloric restriction and delay ageing in 
      metazoans.
    findings:
      - statement: Resveratrol and STACs activate sirtuins and extend lifespan
        supporting_text: resveratrol and other STACs activate sirtuins from 
          Caenorhabditis elegans and Drosophila melanogaster, and extend the 
          lifespan of these animals
      - statement: Lifespan extension is dependent on functional Sir2
        supporting_text: Lifespan extension is dependent on functional Sir2
  - id: PMID:16280150
    title: Overlapping and distinct functions for a Caenorhabditis elegans SIR2 
      and DAF-16/FOXO.
    findings:
      - statement: sir-2.1 null mutants show slight decrease in lifespan and 
          stress sensitivity
        supporting_text: sir-2.1(ok434) mutants show a slight decrease in life 
          span as well as sensitivity to various stresses
      - statement: sir-2.1 required for lifespan extension by caloric 
          restriction
        supporting_text: sir-2.1 is required for life span extension by caloric 
          restriction
      - statement: sir-2.1 and daf-16 have overlapping and distinct roles
        supporting_text: sir-2.1 and daf-16 have overlapping and distinct roles 
          in life span regulation
  - id: PMID:16777605
    title: C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 
      and extend life span.
    findings:
      - statement: 14-3-3 proteins FTT-2 and PAR-5 are SIR-2.1 binding partners
        supporting_text: We identify two C. elegans 14-3-3 proteins as SIR-2.1 
          binding partners
      - statement: 14-3-3 required for SIR-2.1-mediated lifespan extension
        supporting_text: 14-3-3 genes are required for the life-span extension 
          conferred by extra copies of sir-2.1
      - statement: SIR-2.1 binds DAF-16 following heat stress in 
          14-3-3-dependent manner
        supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
          14-3-3-dependent manner
  - id: PMID:16860373
    title: C. elegans 14-3-3 proteins regulate life span and interact with 
      SIR-2.1 and DAF-16/FOXO.
    findings:
      - statement: 14-3-3 proteins physically interact with SIR-2.1 and DAF-16
        supporting_text: We identify two C. elegans 14-3-3 proteins as 
          interacting proteins of a major life span regulator
      - statement: Overexpression of 14-3-3 extends lifespan in DAF-16-dependent
          manner
        supporting_text: overexpression of either 14-3-3 protein (PAR-5 or 
          FTT-2) extends life span and that this is dependent on DAF-16
  - id: PMID:18923081
    title: C. elegans SIR-2.1 translocation is linked to a proapoptotic pathway 
      parallel to cep-1/p53 during DNA damage-induced apoptosis.
    findings:
      - statement: sir-2.1 essential for apoptosis in response to DNA damage
        supporting_text: sir-2.1 is essential for the execution of apoptosis in 
          response to DNA damage
      - statement: sir-2.1 acts parallel to cep-1/p53
        supporting_text: sir-2.1 genetically acts in parallel to the worm 
          p53-like gene cep-1
      - statement: SIR-2.1 translocates from nucleus to cytoplasm during 
          apoptosis
        supporting_text: During apoptosis SIR-2.1 changes its subcellular 
          localization from the nucleus to the cytoplasm
      - statement: SIR-2.1 colocalizes with CED-4 at nuclear periphery
        supporting_text: transiently colocalizes with the C. elegans Apaf-1 
          homolog CED-4 at the nuclear periphery
  - id: PMID:19380489
    title: HIS-24 linker histone and SIR-2.1 deacetylase induce H3K27me3 in the 
      Caenorhabditis elegans germ line.
    findings:
      - statement: SIR-2.1 and HIS-24 essential for H3K27me3 in germline
        supporting_text: SIR-2.1 and HIS-24 that are together essential for 
          maintenance of the H3K27me3 mark in the germ line
      - statement: SIR-2.1 deacetylates H3K9 at subtelomeric regions
        supporting_text: We report that SIR-2.1 deacetylates H3K9 at 
          subtelomeric regions
      - statement: SIR-2.1 and HIS-24 associate with subtelomeric regions
        supporting_text: SIR-2.1 and HIS-24 associate with the subtelomeric 
          regions
  - id: PMID:22393255
    title: Caenorhabditis elegans dosage compensation regulates histone H4 
      chromatin state on X chromosomes.
    findings:
      - statement: SIR-2.1 required for reduction of H4K16ac on 
          dosage-compensated X chromosomes
        supporting_text: Depletion of H4K16ac also requires the conserved 
          histone deacetylase SIR-2.1
      - statement: H4K16 acetylation is underrepresented on hermaphrodite X 
          chromosomes
        supporting_text: H4K16 acetylation (H4K16ac) is underrepresented and 
          H4K20 monomethylation (H4K20me1) is enriched on hermaphrodite X 
          chromosomes
  - id: PMID:23438705
    title: Mitochondrial SIRT4-type proteins in Caenorhabditis elegans and 
      mammals interact with pyruvate carboxylase and other acetylated 
      biotin-dependent carboxylases.
    findings:
      - statement: This paper focuses on SIR-2.2 and SIR-2.3, the SIRT4 
          orthologs
        supporting_text: the Caenorhabditis elegans SIR-2.2 and SIR-2.3 
          orthologs of SIRT4
  - id: PMID:23870130
    title: The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of 
      Mitochondrial UPR and FOXO Signaling.
    findings:
      - statement: NAD+ restoration prevents age-associated decline and promotes
          longevity
        supporting_text: Conversely, genetic or pharmacological restoration of 
          NAD(+) prevents age-associated metabolic decline and promotes 
          longevity in worms
      - statement: Effects dependent on sir-2.1
        supporting_text: These effects are dependent upon the protein 
          deacetylase sir-2.1
      - statement: Involves activation of mitochondrial UPR and DAF-16/FOXO
        supporting_text: involve the induction of mitonuclear protein imbalance 
          as well as activation of stress signaling via the mitochondrial 
          unfolded protein response
  - id: file:worm/sir-2.1/sir-2.1-deep-research-falcon.md
    title: Deep research report on sir-2.1
    findings: []
core_functions:
  - molecular_function:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    description: Core catalytic function. SIR-2.1 is a Class III sirtuin that 
      uses NAD+ as a cofactor to deacetylate protein lysine residues. This 
      activity is central to all its biological functions.
  - molecular_function:
      id: GO:0046969
      label: histone H3K9 deacetylase activity, NAD-dependent
    description: Demonstrated experimentally in germline chromatin where SIR-2.1
      deacetylates H3K9 at subtelomeric regions (PMID:19380489), contributing to
      chromatin silencing.
  - molecular_function:
      id: GO:0046970
      label: histone H4K16 deacetylase activity, NAD-dependent
    description: Required for H4K16ac reduction on dosage-compensated X 
      chromosomes in hermaphrodites (PMID:22393255). Conserved function with 
      yeast Sir2 and mammalian SIRT1.
  - molecular_function:
      id: GO:0071889
      label: 14-3-3 protein binding
    description: SIR-2.1 binds 14-3-3 proteins FTT-2 and PAR-5, which is 
      essential for its role in stress response and lifespan regulation through 
      DAF-16 activation (PMID:16777605, PMID:16860373).
    directly_involved_in:
      - id: GO:0008340
        label: determination of adult lifespan
  - molecular_function:
      id: GO:0003714
      label: transcription corepressor activity
    description: SIR-2.1 is essential for DNA damage-induced germline apoptosis,
      acting in a pathway parallel to CEP-1/p53. It translocates from nucleus to
      cytoplasm during apoptosis (PMID:18923081).
    directly_involved_in:
      - id: GO:0008630
        label: intrinsic apoptotic signaling pathway in response to DNA damage
proposed_new_terms: []
suggested_questions:
  - question: What is the precise substrate specificity of SIR-2.1 for different
      histone lysine residues in different chromatin contexts (germline vs 
      somatic, stressed vs unstressed)?
  - question: How does the controversial nature of sir-2.1 overexpression 
      effects on lifespan relate to genetic background effects and the specific 
      experimental conditions used?
  - question: Does SIR-2.1 deacetylate non-histone substrates in C. elegans, 
      analogous to the known non-histone targets of mammalian SIRT1?
suggested_experiments:
  - description: ChIP-seq analysis of SIR-2.1 binding sites across the genome in
      different tissues and developmental stages to define its chromatin 
      targets.
  - description: Quantitative proteomics to identify acetylated non-histone 
      substrates of SIR-2.1 in C. elegans.
  - description: Structure-function analysis using catalytically inactive 
      mutants to distinguish deacetylase-dependent vs independent functions.
tags:
  - caeel-proteostasis

sir-2.1

Gene Description

Existing Annotations Review

Core Functions

Core catalytic function. SIR-2.1 is a Class III sirtuin that uses NAD+ as a cofactor to deacetylate protein lysine residues. This activity is central to all its biological functions.

Demonstrated experimentally in germline chromatin where SIR-2.1 deacetylates H3K9 at subtelomeric regions (PMID:19380489), contributing to chromatin silencing.

Required for H4K16ac reduction on dosage-compensated X chromosomes in hermaphrodites (PMID:22393255). Conserved function with yeast Sir2 and mammalian SIRT1.

SIR-2.1 binds 14-3-3 proteins FTT-2 and PAR-5, which is essential for its role in stress response and lifespan regulation through DAF-16 activation (PMID:16777605, PMID:16860373).

SIR-2.1 is essential for DNA damage-induced germline apoptosis, acting in a pathway parallel to CEP-1/p53. It translocates from nucleus to cytoplasm during apoptosis (PMID:18923081).

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