title: 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.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Brooke G
authors.initials: BG
authors.lastname: Pantazides
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Karpiuk
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Warren
authors.forename: Claire W
authors.initials: CW
authors.lastname: Hardy
authors.forename: Duc M
authors.initials: DM
authors.lastname: Duong
authors.forename: So-Jeong
authors.initials: SJ
authors.lastname: Park
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.forename: David S
authors.initials: DS
authors.lastname: Yu
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D002460:Cell Line; D002853:Chromatography, Liquid; D003114:Colony-Forming Units Assay; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D004261:DNA Replication / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D051716:Replication Protein A / Q000378:metabolism; D056565:Sirtuin 2 / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D051716:Replication Protein A; C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2
keywords: DNA damage; cell cycle checkpoint; genome maintenance
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