1. SIRT2 directs the replication stress response through CDK9 deacetylation
- Author
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Brooke G. Pantazides, Steven A. Johnsen, Claire W. Hardy, David Gius, Athanassios Vassilopoulos, Duc M. Duong, Seong Hoon Park, Nicholas T. Seyfried, Oleksandra Karpiuk, Hui Zhang, So Jeong Park, David S. Yu, Hyun-Seok Kim, and Matthew D. Warren
- Subjects
DNA Replication ,Cell cycle checkpoint ,Blotting, Western ,Fluorescent Antibody Technique ,SIRT2 ,Cell Line ,Colony-Forming Units Assay ,DNA replication factor CDT1 ,Mice ,Sirtuin 2 ,Tandem Mass Spectrometry ,Replication Protein A ,Animals ,Humans ,Kinase activity ,Replication protein A ,Multidisciplinary ,biology ,DNA replication ,Acetylation ,Cell Cycle Checkpoints ,Biological Sciences ,Cyclin-Dependent Kinase 9 ,Molecular biology ,Cell biology ,Sirtuin ,biology.protein ,Ataxia telangiectasia and Rad3 related ,Chromatography, Liquid - 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.
- Published
- 2013
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