Open AccessALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
Author(s) -
Priyanka Verma,
Yeqiao Zhou,
Zhendong Cao,
Peter Deraska,
Moniher Deb,
Eri Arai,
Weihua Li,
Yue Shao,
Laura N. Puentes,
Yiwen Li,
Sonali Patankar,
Robert H. Mach,
Robert B. Faryabi,
Junwei Shi,
Roger A. Greenberg
Publication year - 2021
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-00624-3
Subject(s) - chromatin , homologous recombination , poly adp ribose polymerase , microbiology and biotechnology , dna repair , dna damage , biology , parp inhibitor , chromatin remodeling , polymerase , dna , chemistry , genetics
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.