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.
| 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 |
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Download this section (compressed HTML)Q: 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)?
Q: How does the controversial nature of sir-2.1 overexpression effects on lifespan relate to genetic background effects and the specific experimental conditions used?
Q: Does SIR-2.1 deacetylate non-histone substrates in C. elegans, analogous to the known non-histone targets of mammalian SIRT1?
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.
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