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: Hui Zhang, Seong-Hoon Park, Brooke G Pantazides, Oleksandra Karpiuk, Matthew D Warren, Claire W Hardy, Duc M Duong, So-Jeong Park, Hyun-Seok Kim, Athanassios Vassilopoulos, Nicholas T Seyfried, Steven A Johnsen, David Gius, David S Yu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 33 Pg. 13546-51 (Aug 13 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23898190 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Replication Protein A
• Cdk9 protein, mouse
• Cyclin-Dependent Kinase 9
• Sirt2 protein, mouse
• Sirtuin 2

Topics

• Acetylation
• Animals
• Blotting, Western
• Cell Cycle Checkpoints (physiology)
• Cell Line
• Chromatography, Liquid
• Colony-Forming Units Assay
• Cyclin-Dependent Kinase 9 (metabolism)
• DNA Replication (physiology)
• Fluorescent Antibody Technique
• Humans
• Mice
• Replication Protein A (metabolism)
• Sirtuin 2 (metabolism)
• Tandem Mass Spectrometry