ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude démontre que la perte de l'expression de ALC1, une protéine impliquée dans le remodelage de la chromatine, augmente la sensibilité aux inhibiteurs de PARP des cellules cancéreuses présentant une déficience du mécanisme de réparation de l'ADN par recombinaison homologue
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.
Nature Cell Biology 2021