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SIRT2 directs the replication stress response through CDK9 deacetylation

Title
SIRT2 directs the replication stress response through CDK9 deacetylation
Authors
Zhang H.Park S.-H.Pantazides B.G.Karpiuk O.Warren M.D.Hardy C.W.Duong D.M.Park S.-J.Kim H.-S.Vassilopoulos A.Seyfried N.T.Johnsen S.A.Gius D.Yu D.S.
Ewha Authors
김현석
SCOPUS Author ID
김현석scopus
Issue Date
2013
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424JCR Link
Citation
vol. 110, no. 33, pp. 13546 - 13551
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Sirtuin 2 (SIRT2) is a sirtuin family deacetylase that directs acetylome signaling, protects genome integrity, and is a murine tumor suppressor. We show that SIRT2 directs replication stress responses by regulating the activity of cyclin-dependent kinase 9 (CDK9), a protein required for recovery from replication arrest. SIRT2 deficiency results in replication stress sensitivity, impairment in recovery from replication arrest, spontaneous accumulation of replication protein A to foci and chromatin, and a G2/M checkpoint deficit. SIRT2 interacts with and deacetylates CDK9 at lysine 48 in response to replication stress in a manner that is partially dependent on ataxia telangiectasia and Rad3 related (ATR) but not cyclin T or K, thereby stimulating CDK9 kinase activity and promoting recovery from replication arrest. Moreover, wild-type, but not acetylated CDK9, alleviates the replication stress response impairment of SIRT2 deficiency. Collectively, our results define a function for SIRT2 in regulating checkpoint pathways that respond to replication stress through deacetylation of CDK9, providing insight into how SIRT2 maintains genome integrity and a unique mechanism by which SIRT2 may function, at least in part, as a tumor suppressor protein.
DOI
10.1073/pnas.1301463110
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일반대학원 > 바이오융합과학과 > Journal papers
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