ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
Balmus G, Pilger D, Coates J, Demir M, Sczaniecka-Clift M, Barros A, Woods M, Fu B,Yang F, Chen E, Ostermaier M, Stankovic T, Ponstingl H, Herzog M, Yusa K, Munoz-Martinez F, Durant ST, Galanty Y, Beli P, Adams DJ, Bradley A, Metzakopian E, Forment JV, Jackson SP. (2018) BioRxiv
Mutations in the ATM tumor suppressor confer hypersensitivity to DNA-damaging agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase poison topotecan. Thus, we establish that loss of terminal components of the non-homologous end-joining (NHEJ) machinery or the BRCA1-A complex specifically confers topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase inhibitor olaparib is due to delayed homologous recombination repair at DNA-replication-fork-associated double-strand breaks (DSBs), resulting in toxic NHEJ-mediated chromosome fusions. Accordingly, restoring legitimate repair in ATM-deficient cells, either by preventing NHEJ DNA ligation or by enhancing DSB-resection by BRCA1-A complex inactivation, markedly suppresses this toxicity. Our work suggests opportunities for patient stratification in ATM-deficient cancers and when using ATM inhibitors in the clinic, and identifies additional therapeutic vulnerabilities that might be exploited when such cancers evolve drug resistance.