| Literature DB >> 26854234 |
Hui Zhang1, PamelaSara E Head1, Waaqo Daddacha1, Seong-Hoon Park2, Xingzhe Li1, Yunfeng Pan1, Matthew Z Madden1, Duc M Duong3, Maohua Xie1, Bing Yu1, Matthew D Warren1, Elaine A Liu1, Vishal R Dhere1, Chunyang Li1, Ivan Pradilla1, Mylin A Torres1, Ya Wang1, William S Dynan4, Paul W Doetsch4, Xingming Deng1, Nicholas T Seyfried3, David Gius2, David S Yu5.
Abstract
The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase checkpoint pathway maintains genome integrity; however, the role of the sirtuin 2 (SIRT2) acetylome in regulating this pathway is not clear. We found that deacetylation of ATR-interacting protein (ATRIP), a regulatory partner of ATR, by SIRT2 potentiates the ATR checkpoint. SIRT2 interacts with and deacetylates ATRIP at lysine 32 (K32) in response to replication stress. SIRT2 deacetylation of ATRIP at K32 drives ATR autophosphorylation and signaling and facilitates DNA replication fork progression and recovery of stalled replication forks. K32 deacetylation by SIRT2 further promotes ATRIP accumulation to DNA damage sites and binding to replication protein A-coated single-stranded DNA (RPA-ssDNA). Collectively, these results support a model in which ATRIP deacetylation by SIRT2 promotes ATR-ATRIP binding to RPA-ssDNA to drive ATR activation and thus facilitate recovery from replication stress, outlining a mechanism by which the ATR checkpoint is regulated by SIRT2 through deacetylation.Entities:
Keywords: ATR; ATRIP; DNA damage response; DNA repair; DNA replication; SIRT2; acetylome; cell cycle; checkpoint; metabolism; replication stress; sirtuin
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Year: 2016 PMID： 26854234 PMCID： PMC4758896 DOI： 10.1016/j.celrep.2016.01.018
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423