SIRT2 directs the replication stress response through CDK9 deacetylation.

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.

authors

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 DS

doi

10.1073/pnas.1301463110

subject

Has Abstract

pub_date

2013-08-13 00:00:00

pages

13546-51

issue

33

eissn

0027-8424

issn

1091-6490

pii

1301463110

journal_volume

110

pub_type

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