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dc.contributor.authorChiang, Wei-Chung
dc.contributor.authorTishkoff, Daniel X.
dc.contributor.authorYang, Bo
dc.contributor.authorGrady, Joshua Terrence Wilson
dc.contributor.authorYu, Xiaokun
dc.contributor.authorMazer, Travis
dc.contributor.authorEckersdorff, Mark
dc.contributor.authorGygi, Steven P.
dc.contributor.authorLombard, David B.
dc.contributor.authorHsu, Ao-Lin
dc.date.accessioned2013-04-10T20:13:08Z
dc.date.issued2012
dc.identifier.citationChiang, Wei-Chung, Daniel X. Tishkoff, Bo Yang, Joshua Wilson-Grady, Xiaokun Yu, Travis Mazer, Mark Eckersdorff, Steven P. Gygi, David B. Lombard, and Ao-Lin Hsu. 2012. C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. PLoS Genetics 8(9): e1002948.en_US
dc.identifier.issn1553-7390en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10524339
dc.description.abstractFoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4—homolog of mammalian SIRT6 and SIRT7 proteins—promotes DAF-16–dependent transcription and stress-induced DAF-16 nuclear localization. SIR-2.4 is required for resistance to multiple stressors: heat shock, oxidative insult, and proteotoxicity. By contrast, SIR-2.4 is largely dispensable for DAF-16 nuclear localization and function in response to reduced insulin/IGF-1-like signaling. Although acetylation is known to regulate localization and activity of mammalian FoxO proteins, this modification has not been previously described on DAF-16. We find that DAF-16 is hyperacetylated in sir-2.4 mutants. Conversely, DAF-16 is acetylated by the acetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalytic mutant efficiently rescues the DAF-16 localization defect in sir-2.4 null animals. Acetylation of DAF-16 by CBP-1 in vitro is inhibited by either wild-type or mutant SIR-2.4, suggesting that SIR-2.4 regulates DAF-16 acetylation indirectly, by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SIR-2.4 as a critical regulator of DAF-16 specifically in the context of stress responses. Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pgen.1002948en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441721/pdf/en_US
dash.licenseLAA
dc.subjectBiologyen_US
dc.subjectGeneticsen_US
dc.subjectGene Expressionen_US
dc.subjectGenetic Mutationen_US
dc.subjectMolecular Geneticsen_US
dc.subjectModel Organismsen_US
dc.subjectAnimal Modelsen_US
dc.titleC. elegans SIRT6/7 Homolog SIR-2.4 Promotes DAF-16 Relocalization and Function during Stressen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Geneticsen_US
dash.depositing.authorGygi, Steven P.
dc.date.available2013-04-10T20:13:08Z
dc.identifier.doi10.1371/journal.pgen.1002948*
dash.contributor.affiliatedWilson-Grady, Joshua
dash.contributor.affiliatedGygi, Steven


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