@article{9ef13c3fa50249d0a7cda8addb702c22,
title = "ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA",
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.",
keywords = "ATR, ATRIP, Acetylome, Cell cycle, Checkpoint, DNA damage response, DNA repair, DNA replication, Metabolism, Replication stress, SIRT2, Sirtuin",
author = "Hui Zhang and Head, {Pamela Sara E.} and Waaqo Daddacha and Park, {Seong Hoon} and Xingzhe Li and Yunfeng Pan and Madden, {Matthew Z.} and Duong, {Duc M.} and Maohua Xie and Bing Yu and Warren, {Matthew D.} and Liu, {Elaine A.} and Dhere, {Vishal R.} and Chunyang Li and Ivan Pradilla and Torres, {Mylin A.} and Ya Wang and Dynan, {William S.} and Doetsch, {Paul W.} and Xingming Deng and Seyfried, {Nicholas T.} and David Gius and Yu, {David S.}",
note = "Funding Information: We thank members of D.S.Y.{\textquoteright}s lab for helpful discussion. We thank Dr. Akira Matsuura for ATRIP-GFP and David Cortez for HA-ATRIP, His-RPA, and GST-ATRIP 1–107 plasmids. This work was supported by NIH/National Cancer Institute (NCI) K08CA143902, R01CA178999, and R01CA178999S1 to D.S.Y and R01CA98239 to W.S.D.; Emory University Research Committee (URC) Pilot Award to D.S.Y.; and Georgia Research Alliance (GRA) Cancer Scientist 11072 to D.S.Y. DG is supported by NCI-2R01CA152601-06A1, 1R01CA152799-01A1, 1R01CA168292-01A1, 1R01CA16383801A1, and Avon Foundation for Breast Cancer Research and Care Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. P.E.H, W.D., S.P., and X.L. contributed equally to this manuscript. DG is supported by NCI-2R01CA152601-06A1, NCI-1R01CA152799-01A1, NCI-1R01CA168292-01A1, and 1R01CA16383801A1. Funding Information: We thank members of D.S.Y.{\textquoteright}s lab for helpful discussion. We thank Dr. Akira Matsuura for ATRIP-GFP and David Cortez for HA-ATRIP, His-RPA, and GST-ATRIP 1–107 plasmids. This work was supported by NIH/National Cancer Institute (NCI) K08CA143902, R01CA178999, and R01CA178999S1 to D.S.Y and R01CA98239 to W.S.D.; Emory University Research Committee (URC) Pilot Award to D.S.Y.; and Georgia Research Alliance (GRA) Cancer Scientist 11072 to D.S.Y. DG is supported by NCI-2R01CA152601-06A1, 1R01CA152799-01A1, 1R01CA168292-01A1, 1R01CA16383801A1, and Avon Foundation for Breast Cancer Research and Care Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. P.E.H, W.D., S.P., and X.L. contributed equally to this manuscript. DG is supported by NCI-2R01CA152601-06A1, NCI-1R01CA152799-01A1, NCI-1R01CA168292-01A1, and 1R01CA16383801A1. Publisher Copyright: {\textcopyright} 2016 The Authors.",
year = "2016",
month = feb,
day = "16",
doi = "10.1016/j.celrep.2016.01.018",
language = "English (US)",
volume = "14",
pages = "1435--1447",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}