ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

Jianfeng Shen, Yang Peng, Leizhen Wei, Wei Zhang, Lin Yang, Li Lan, Prabodh Kapoor, Zhenlin Ju, Qianxing Mo, Ie Ming Shih, Ivan P. Uray, Xiangwei Wu, Powel H. Brown, Xuetong Shen, Gordon B. Mills, Guang Peng

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)752-767
Number of pages16
JournalCancer discovery
Volume5
Issue number7
DOIs
StatePublished - Jul 2015

ASJC Scopus subject areas

  • Oncology

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