RESEARCH ARTICLE ARID1A Defi ciency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

ABSTRACT ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identifi ed 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 defi ciency 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 effi cient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A defi ciency 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 identifi ed 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 exhibi