SIRT1 negatively regulates HDAC1-dependent transcriptional repression by the RBP1 family of proteins.
Both RBP1 and the highly related protein BCAA play a role in the induction of growth arrest and cellular senescence via mechanisms involving transcriptional repression. While investigating the transcriptional repression activities of RBP1, we observed a genetic link between RBP1 and SIR2. Further work uncovered an interaction between RBP1 family proteins and the mammalian homologue of SIR2, SIRT1. Interestingly, the HDAC-dependent transcriptional repression domain of RBP1 proteins, termed R2, is necessary and sufficient for the interaction with SIRT1. In vitro and in vivo binding studies indicated that the p33(ING1b) and p33(ING2) subunits of the mSIN3A/HDAC1 complex are responsible for the recruitment of SIRT1 to the R2 domain. To investigate the biological relevance of this interaction, we used the sirtuin activator resveratrol and the sirtuin inhibitor sirtinol in transcriptional repression assays and demonstrated that SIRT1 activity negatively regulates R2-mediated transcriptional repression activity. We therefore propose a novel mechanism of class I HDAC regulation by a class III HDAC. Explicitly, SIRT1 is recruited by ING proteins and inhibits R2-associated mSIN3A/HDAC1 transcriptional repression activity.
Binda
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Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Nassif
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Branton
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D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009284:Naphthols / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077185:Resveratrol; D054840:Retinol-Binding Proteins, Cellular / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D001549:Benzamides; D018398:Homeodomain Proteins; C501503:ING1 protein, human; C444654:ING2 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009284:Naphthols; D009687:Nuclear Proteins; C518456:RBP1 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D054840:Retinol-Binding Proteins, Cellular; C099683:SIN3A transcription factor; D013267:Stilbenes; D025521:Tumor Suppressor Proteins; C439060:sirtinol; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000077185:Resveratrol