PubMed Journals: J Biol Chem
Source: PMID: 15632193
⇦ ⇨ J Biol Chem. 2005 Mar 18;280(11):10264-76.
⇩ Epub 2005 Jan 4.
SIRT1 deacetylation and repression of p300
involves lysine residues 1020/1024 within
the cell cycle regulatory domain 1.
Bouras T(1), Fu M, Sauve AA, Wang F, Quong
AA, Perkins ND, Hay RT, Gu W, Pestell RG.
(1) Department of Oncology, Lombardi Comprehensive
Cancer Center, Georgetown University, 3970
Reservoir Rd.,Washington, DC 20057, USA.
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.
DOI: 10.1074/jbc.M408748200 PMID: 15632193
[Indexed for MEDLINE]