ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA.
ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA.
复制标题
DOI：
10.1016/j.celrep.2016.01.018
复制
发表时间：
2016-02-16
期刊：
影响因子：
8.8
通讯作者：
Yu DS
中科院分区：
文献类型：
--
作者：
Zhang H;Head PE;Daddacha W;Park SH;Li X;Pan Y;Madden MZ;Duong DM;Xie M;Yu B;Warren MD;Liu EA;Dhere VR;Li C;Pradilla I;Torres MA;Wang Y;Dynan WS;Doetsch PW;Deng X;Seyfried NT;Gius D;Yu DS
共济失调毛细血管扩张突变和rad3相关（ATR）激酶检查点通路维持基因组完整性；然而，sirtuin 2 （SIRT2）乙酰化酶在调节这一途径中的作用尚不清楚。我们发现，ATR的调控伙伴ATR相互作用蛋白（ATRIP）被SIRT2去乙酰化可以增强ATR检查点。SIRT2与赖氨酸32 （K32）上的ATRIP相互作用并使其去乙酰化，以响应复制应激。K32位点的ATRIP的SIRT2去乙酰化驱动ATR自磷酸化和信号传导，促进DNA复制叉的进展和停滞复制叉的恢复。SIRT2的K32去乙酰化进一步促进ATRIP积累到DNA损伤位点并结合到复制蛋白a包被的单链DNA （RPA-ssDNA）上。总之，这些结果支持了一个模型，其中SIRT2的ATRIP去乙酰化促进ATR-ATRIP与RPA-ssDNA结合，从而驱动ATR激活，从而促进从复制应激中恢复，概述了SIRT2通过去乙酰化调节ATR检查点的机制。Zhang等人证明，SIRT2在保守赖氨酸32位点使ATRIP去乙酰化，促进ATR-ATRIP与RPA-ssDNA结合，从而驱动ATR活化，从而促进从复制应激中恢复。
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. Zhang et al. demonstrate that ATRIP deacetylation at conserved lysine 32 by SIRT2 promotes ATR-ATRIP binding to RPA-ssDNA to drive ATR activation and thus facilitate recovery from replication stress.