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

T Bouras, M F Fu, A A Sauve, F Wang, A A Quong, N D Perkins, R T Hay, W Gu, R G Pestell

Research output: Contribution to journalArticlepeer-review

294 Citations (Scopus)

Abstract

The SIR2 family of nicotinamide adenosine dinucleotide (NAD)-dependent deacetylases modulates diverse biological functions in different species, including longevity, apoptosis, cell cycle exit, and cellular differentiation. SIRT1, the closest mammalian ortholog of the yeast SIR2 ( silent information regulator 2) gene, represses several transcription factors, including p53, NF kappa B and forkhead proteins. The p300 protein serves as a rate-limiting transcriptional cointegrator of diverse transcription factors either to activate or to repress transcription through modular subdomains. Herein, SIRT1 physically interacted with and repressed p300 transactivation, requiring the NAD-dependent deacetylase activity of SIRT1. SIRT1 repression involved the CRD1 transcriptional repression domain of p300. Two residues within the CRD1 domain (Lys-1020 and Lys-1024) were required for SIRT1 repression and served as substrates for SIRT1 deacetylation. These residues also serve as acceptor lysines for modification by the ubiquitin-like SUMO protein. The SUMO-specific protease SSP3 relieved SIRT1 repression of p300. SSP3 antagonism of SIRT1 required the SUMO-deconjugating function of SSP3. Thus, p300 serves as a deacetylase substrate for SIRT1 through a conserved SUMO consensus motif. Because p300 is a limiting transcriptional cofactor, deacetylation and repression of p300 by SIRT1 may serve an important integration point during metabolism and cellular differentiation.

Original languageEnglish
Pages (from-to)10264-10276
Number of pages13
JournalJournal of Biological Chemistry
Volume280
DOIs
Publication statusPublished - 18 Mar 2005

Keywords

  • CREB-BINDING-PROTEIN
  • KAPPA-B ACTIVATION
  • HISTONE ACETYLTRANSFERASE
  • TRANSCRIPTIONAL REPRESSION
  • SUMO-1 MODIFICATION
  • GENE
  • CBP
  • P53
  • ACETYLATION
  • UBIQUITIN

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