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Author Notes:

Correspondence: dsyu@emory.edu

Conceptualization, H.Z., M.A.T., Y.W., W.S.D., P.W.D., Z.D., N.T.S., D.G., and D.S.Y.

Investigation, H.Z., P.E.H., W.D., S.P., X.L., Y.P., M.Z.M., D.M.D., M.X., B.Y., M.D.W., E.A.L., V.R.D., C.L., I.P., and M.A.T.

Writing – Original Draft, H.Z. and D.S.Y.

Writing – Review and Editing, H.Z., P.E.H., W.D., S.P., X.L., Y.P., M.Z.M., D.M.D., M.X., B.Y., M.D.W., E.A.L., V.R.D., C.L., I.P., M.A.T., Y.W., W.S.D., P.W.D., X.D., N.T.S., D.G., and D.S.Y.

Supervision, M.A.T., Y.W., W.S.D., P.W., X.D., N.T.S., D.G., and D.S.Y.

Funding Acquisition, D.S.Y.

P.E.H, W.D., S.P., and X.L. contributed equally to this manuscript.

We thank members of D.S.Y.’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.

Research Funding:

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.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • REPLICATION PROTEIN-A
  • DNA-DAMAGE CHECKPOINT
  • DOUBLE-STRAND BREAKS
  • S-PHASE CHECKPOINT
  • ATAXIA-TELANGIECTASIA
  • GENOME INTEGRITY
  • STRESS-RESPONSE
  • TOPBP1
  • SIRTUINS
  • COMPLEX

ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA

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Journal Title:

Cell Reports

Volume:

Volume 14, Number 6

Publisher:

, Pages 1435-1447

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2016 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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