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.
journal_name
Proc Natl Acad Sci U S Aauthors
Zhang H,Park SH,Pantazides BG,Karpiuk O,Warren MD,Hardy CW,Duong DM,Park SJ,Kim HS,Vassilopoulos A,Seyfried NT,Johnsen SA,Gius D,Yu DSdoi
10.1073/pnas.1301463110subject
Has Abstractpub_date
2013-08-13 00:00:00pages
13546-51issue
33eissn
0027-8424issn
1091-6490pii
1301463110journal_volume
110pub_type
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