2022.06.13 Chromatin vulnerabilities in BRCA mutant cancers

2022-07-06 16:01:24



    : Chromatin vulnerabilities in BRCA mutant cancers

报告人Professor Roger Greenberg

Department of Cancer Biology, University of Pennsylvania


    : ZOOM线上报告

Meeting ID: 910 9636 7823


主持人: 齐志 研究员


The response to Poly (ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair mechanisms and the abundance of lesions that trap PARP enzymes on chromatin. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. PARP dependent chromatin decondensation was reported 40 years ago yet has remained enigmatic in relation to its role in genome integrity and genetic interactions with homologous recombination deficiency. Using a CRISPR based screen, we identify the PAR-binding Snf2-like ATPase, ALC1/CHD1L, as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of BRCA mutant cells and enhanced their sensitivity to PARPi by up to 250-fold, while overcoming several known resistance mechanisms. ALC1 loss was not epistatic to other repair pathways that execute the PARPi response. Instead, ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of repair factors. This resulted in an accumulation of replication associated DNA gaps that trap PARP1 and PARP2, and a reliance on HR. Moreover, ALC1 deficiency overcame several known PARPi resistance mechanisms. These findings establish PAR-dependent chromatin remodeling as a mechanistically distinct aspect of PARPi responses, implicating ALC1 inhibition as a new approach to overcome therapeutic resistance in HR-deficient cancers.


Professor Roger Greenberg received his MD and Ph.D. in Biology and Medicine from Albert Einstein College of Medicine in 2000. He was promoted to full Professor in Department of Cancer Biology of University of Pennsylvania in 2017. In University of Pennsylvania, Greenberg is also the Director of Basic Science, Basser Center for BRCA and Center for Genome Integrity. His laboratory investigates fundamental DNA damage response mechanisms and their impact on cancer etiology and therapeutic response.