ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells.

The response to poly(ADP-ribose) polymerase inhibitors is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap enzymes. It remains unclear, however, if the established role of Pduanyu37 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 toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to Pduanyu37i 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 Pduanyu37 trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of Pduanyu37i responses and therapeutic target in HR-deficient cancers.

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