Cell Reports (Feb 2016)
ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA
- Hui Zhang,
- PamelaSara 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
Affiliations
- Hui Zhang
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- PamelaSara E. Head
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Waaqo Daddacha
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Seong-Hoon Park
- Department of Radiation Oncology and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Xingzhe Li
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Yunfeng Pan
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Matthew Z. Madden
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Duc M. Duong
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
- Maohua Xie
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Bing Yu
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Matthew D. Warren
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Elaine A. Liu
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Vishal R. Dhere
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Chunyang Li
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Ivan Pradilla
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Mylin A. Torres
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Ya Wang
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- William S. Dynan
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Paul W. Doetsch
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Xingming Deng
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Nicholas T. Seyfried
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
- David Gius
- Department of Radiation Oncology and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- David S. Yu
- Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
- DOI
- https://doi.org/10.1016/j.celrep.2016.01.018
- Journal volume & issue
-
Vol. 14,
no. 6
pp. 1435 – 1447
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
- sirtuin
- metabolism
- SIRT2
- ATR
- ATRIP
- replication stress
- DNA replication
- DNA damage response
- DNA repair
- acetylome
- cell cycle
- checkpoint
