Nat Cell Biol. 2021 Feb;23(2):160-171. doi: 10.1038/s41556-020-00624-3. | PubMed

Priyanka Verma¹, Yeqiao Zhou², Zhendong Cao³, Peter V Deraska¹, Moniher Deb¹, Eri Arai³, Weihua Li¹, Yue Shao¹, Laura Puentes⁴, Yiwen Li¹, Sonali Patankar¹, Robert H Mach⁴, Robert B Faryabi², Junwei Shi⁵, Roger A Greenberg⁶

1. Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2. Departments of Pathology and Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3. Department of Cancer Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5. Department of Cancer Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jushi@upenn.edu.
6. Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rogergr@pennmedicine.upenn.edu.

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.

Presented By Roger Greenberg