SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1.
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, NFkappaB 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.
Bouras
Toula
T
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Rd.,Washington, DC 20057, USA.
Fu
Maofu
M
Sauve
Anthony A
AA
Wang
Fang
F
Quong
Andrew A
AA
Perkins
Neil D
ND
Hay
Ronald T
RT
Gu
Wei
W
Pestell
Richard G
RG
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D050881:E1A-Associated p300 Protein; D005347:Fibroblasts / Q000166:cytology; D017930:Genes, Reporter; D005822:Genetic Vectors; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008239:Lysine / Q000737:chemistry*; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D012190:Retroviridae / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D016328:NF-kappa B; D009687:Nuclear Proteins; D009841:Oligonucleotides; D010455:Peptides; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D009243:NAD; D012313:RNA; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D012697:Serine Endopeptidases; C460219:Stomoxys serine protease 3; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine