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

Resultado de la investigación: Articlerevisión exhaustiva

71 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)13546-13551
Número de páginas6
PublicaciónProceedings of the National Academy of Sciences of the United States of America
Volumen110
N.º33
DOI
EstadoPublished - ago. 13 2013
Publicado de forma externa

ASJC Scopus subject areas

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