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.
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Hui
authors: H
authors: Zhang
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: PamelaSara E
authors: PE
authors: Head
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Waaqo
authors: W
authors: Daddacha
authors: Department of Radiation Oncology and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Seong-Hoon
authors: SH
authors: Park
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Xingzhe
authors: X
authors: Li
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Yunfeng
authors: Y
authors: Pan
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Matthew Z
authors: MZ
authors: Madden
authors: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Duc M
authors: DM
authors: Duong
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Maohua
authors: M
authors: Xie
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Bing
authors: B
authors: Yu
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Matthew D
authors: MD
authors: Warren
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Elaine A
authors: EA
authors: Liu
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Vishal R
authors: VR
authors: Dhere
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Chunyang
authors: C
authors: Li
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Ivan
authors: I
authors: Pradilla
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Mylin A
authors: MA
authors: Torres
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Ya
authors: Y
authors: Wang
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: William S
authors: WS
authors: Dynan
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Paul W
authors: PW
authors: Doetsch
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Xingming
authors: X
authors: Deng
authors: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Nicholas T
authors: NT
authors: Seyfried
authors: Department of Radiation Oncology and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: David
authors: D
authors: Gius
authors: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: dsyu@emory.edu.
authors: David S
authors: DS
authors: Yu
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D051716:Replication Protein A / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C521194:ATRIP protein, human; D048868:Adaptor Proteins, Signal Transducing; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D051716:Replication Protein A; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C474199:SIRT2 protein, human; D056565:Sirtuin 2
keywords: ATR; ATRIP; DNA damage response; DNA repair; DNA replication; SIRT2; acetylome; cell cycle; checkpoint; metabolism; replication stress; sirtuin