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ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors
Open accessPublished version of a preprint
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. 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
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“ARID1A regulates DNA damage checkpoints and sensitizes cells to DNA damage response (DDR) targeting agents67–69.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [68]
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Metadata
- Authors
- Shen, J., Peng, Y., Wei, L., Zhang, W., Yang, L., Lan, L., Kapoor, P., Ju, Z., Mo, Q., Shih, I.-M., Uray, I. P., Wu, X., Brown, P. H., Shen, X., Mills, G. B., & Peng, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Pittsburgh (US)
- Baylor College of Medicine (US)
- Johns Hopkins University (US)
- 1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Corresponding author
- Peng, Guang
- ORCID
- Venue
- Cancer Discovery
- Published
- 2015-07-01
- Volume
- 5
- Issue
- 7
- Pages
- 752-767
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4497871
- OpenAlex
- W2123454509
- Cited by
- 522
- References
- 61
- Citations by year
- 2026: 33 · 2025: 53 · 2024: 59 · 2023: 56 · 2022: 53 · 2021: 71 · 2020: 62 · 2019: 43 · 2018: 36 · 2017: 28 · 2016: 24 · 2015: 3
- FWCI
- 13.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (CA 016672, P50CA098258, P50-CA83639, R00CA149186, K99CA149186, P50CA083639, P30CA016672, R01CA181663)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- ARID1A, SWI/SNF complex, DNA damage checkpoint, PARP inhibitors, ATR kinase, DNA double-strand breaks, tumor suppressor, drug sensitivity
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Breast Neoplasms, DNA Damage, DNA-Binding Proteins, Female, Humans, Lung Neoplasms, Male, Nuclear Proteins, Transcription Factors, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Line, Tumor, Mice, DNA Breaks, Double-Stranded, Ataxia Telangiectasia Mutated Proteins
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