SIRT2 directs the replication stress response through CDK9 deacetylation

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13546-13551
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number33
DOIs
StatePublished - Aug 13 2013

Keywords

  • Cell cycle checkpoint
  • DNA damage
  • Genome maintenance

ASJC Scopus subject areas

  • General

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    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. (2013). SIRT2 directs the replication stress response through CDK9 deacetylation. Proceedings of the National Academy of Sciences of the United States of America, 110(33), 13546-13551. https://doi.org/10.1073/pnas.1301463110