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

Hui Zhang; Pamela Sara E. Head; Waaqo Daddacha; Seong Hoon Park; Xingzhe Li; Yunfeng Pan; Matthew Z. Madden; Duc M. Duong; Maohua Xie; Bing Yu; Matthew D. Warren; Elaine A. Liu; Vishal R. Dhere; Chunyang Li; Ivan Pradilla; Mylin A. Torres; Ya Wang; William S. Dynan; Paul W. Doetsch; Xingming Deng; Nicholas T. Seyfried; David Gius; David S. Yu

doi:10.1016/j.celrep.2016.01.018

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

Hui Zhang, Pamela Sara E. Head, Waaqo Daddacha, Seong Hoon Park, Xingzhe Li, Yunfeng Pan, Matthew Z. Madden, Duc M. Duong, Maohua Xie, Bing Yu, Matthew D. Warren, Elaine A. Liu, Vishal R. Dhere, Chunyang Li, Ivan Pradilla, Mylin A. Torres, Ya Wang, William S. Dynan, Paul W. Doetsch, Xingming DengNicholas T. Seyfried, David Gius, David S. Yu

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1435-1447
Number of pages	13
Journal	Cell Reports
Volume	14
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2016.01.018
State	Published - Feb 16 2016
Externally published	Yes

Keywords

ATR
ATRIP
Acetylome
Cell cycle
Checkpoint
DNA damage response
DNA repair
DNA replication
Metabolism
Replication stress
SIRT2
Sirtuin

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2016.01.018

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Zhang, H., Head, P. S. E., Daddacha, W., Park, S. H., Li, X., Pan, Y., Madden, M. Z., Duong, D. M., Xie, M., Yu, B., Warren, M. D., Liu, E. A., Dhere, V. R., Li, C., Pradilla, I., Torres, M. A., Wang, Y., Dynan, W. S., Doetsch, P. W., ... Yu, D. S. (2016). ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA. Cell Reports, 14(6), 1435-1447. https://doi.org/10.1016/j.celrep.2016.01.018

Zhang, H, Head, PSE, 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 2016, 'ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA', Cell Reports, vol. 14, no. 6, pp. 1435-1447. https://doi.org/10.1016/j.celrep.2016.01.018

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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 = "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",

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TY - JOUR

T1 - ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA

AU - Zhang, Hui

AU - Head, Pamela Sara E.

AU - Daddacha, Waaqo

AU - Park, Seong Hoon

AU - Li, Xingzhe

AU - Pan, Yunfeng

AU - Madden, Matthew Z.

AU - Duong, Duc M.

AU - Xie, Maohua

AU - Yu, Bing

AU - Warren, Matthew D.

AU - Liu, Elaine A.

AU - Dhere, Vishal R.

AU - Li, Chunyang

AU - Pradilla, Ivan

AU - Torres, Mylin A.

AU - Wang, Ya

AU - Dynan, William S.

AU - Doetsch, Paul W.

AU - Deng, Xingming

AU - Seyfried, Nicholas T.

AU - Gius, David

AU - Yu, David S.

PY - 2016/2/16

Y1 - 2016/2/16

N2 - 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.

AB - 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.

KW - ATR

KW - ATRIP

KW - Acetylome

KW - Cell cycle

KW - Checkpoint

KW - DNA damage response

KW - DNA repair

KW - DNA replication

KW - Metabolism

KW - Replication stress

KW - SIRT2

KW - Sirtuin

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UR - http://www.scopus.com/inward/citedby.url?scp=84958102018&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.01.018

DO - 10.1016/j.celrep.2016.01.018

M3 - Article

C2 - 26854234

AN - SCOPUS:84958102018

SN - 2211-1247

VL - 14

SP - 1435

EP - 1447

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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