title: ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors.
abstract: ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.
  
  
  CONCLUSIONS
  ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yang
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Leizhen
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Medical Oncology, Tongji Hospital, Tongji Medical College, The Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Li
authors.initials: L
authors.lastname: Lan
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Prabodh
authors.initials: P
authors.lastname: Kapoor
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Uray
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xuetong
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Medical Oncology, Tongji Hospital, Tongji Medical College, The Huazhong University of Science and Technology, Wuhan, P.R. China. gpeng@mdanderson.org.
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000172:deficiency*; D023041:Xenograft Model Antitumor Assays
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014157:Transcription Factors; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins