ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors
| Autor: | Li Lan, Gordon B. Mills, Prabodh Kapoor, Ivan P. Uray, Xuetong Shen, Guang Peng, Qianxing Mo, Zhenlin Ju, Jianfeng Shen, Yang Peng, Xiangwei Wu, Ie Ming Shih, Leizhen Wei, Powel H. Brown, Lin Yang, Wei Zhang |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Lung Neoplasms ARID1A DNA damage Poly ADP ribose polymerase Oncology and Carcinogenesis Breast Neoplasms Ataxia Telangiectasia Mutated Proteins Poly(ADP-ribose) Polymerase Inhibitors Biology Article Chromatin remodeling Cell Line Mice Double-Stranded Rare Diseases Clinical Research Cell Line Tumor Genetics medicine Animals Humans 2.1 Biological and endogenous factors DNA Breaks Double-Stranded Elméleti orvostudományok Aetiology Cancer Tumor Kinase DNA Breaks Human Genome Nuclear Proteins Orvostudományok G2-M DNA damage checkpoint HCT116 Cells medicine.disease Xenograft Model Antitumor Assays Molecular biology DNA-Binding Proteins Oncology Cancer cell Cancer research Female biological phenomena cell phenomena and immunity DNA Damage Transcription Factors |
| Zdroj: | Cancer discovery, vol 5, iss 7 |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-14-0849 |
| Popis: | 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. Significance: 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. Cancer Discov; 5(7); 752–67. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 681 |
| Databáze: | OpenAIRE |
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