@article{676fc306ac154a49b7dc460ea85d6fe7,
title = "ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells",
abstract = "The response to poly(ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication-associated DNA damage, increased PARP trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers.",
author = "Priyanka Verma and Yeqiao Zhou and Zhendong Cao and Deraska, {Peter V.} and Moniher Deb and Eri Arai and Weihua Li and Yue Shao and Laura Puentes and Yiwen Li and Sonali Patankar and Mach, {Robert H.} and Faryabi, {Robert B.} and Junwei Shi and Greenberg, {Roger A.}",
note = "Funding Information: We thank D. Durocher (University of Toronto, Lunenfeld) for sharing hTERT-RPE1 p53−/− BRCA1−/− cells and controls, J. and R. Connaway (Stowers) for ALC1 plasmids, K. Caldecott (University of Sussex) for sharing the GFP-XRCC1 plasmid and hTERT-RPE1 XRCC1−/− and parental control cells, N. Lakin (University of Oxford) for sharing U-2 OS PARP1−/−, PARP2−/− and PARP1/2−/− cells, N. Johnson (Fox Chase) for SUM149PT BRCA1 reversion mutant cell lines and helpful discussions on mouse xenograft experiments and M. Altmeyer (University of Zurich) for helpful suggestions on PARP1 trapping experiments. This work was supported by NIH grants GM101149 and CA17494 (R.A.G.), who is also supported by funds from the Penn Center for Genome Integrity, the Basser Center for BRCA, a V Foundation Team Convergence Award and a Gray Foundation Team Science Award. P.V. was supported by the Ann and Sol Schreiber Mentored Investigator Award (Ovarian Cancer Research Fund Alliance) and pilot funds from the Ovarian Cancer Translational Center for Excellence (UPenn). J.S. was supported by the Michele and Kevah Konner Award through the Basser Center for BRCA. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = feb,
doi = "10.1038/s41556-020-00624-3",
language = "English",
volume = "23",
pages = "160--171",
journal = "Nature Cell Biology",
issn = "1465-7392",
number = "2",
}