This allows more time for DNA repair, which in the case of DSBs mainly involves the use of non-homologous end-joining (NHEJ) or homologous recombination (HR) repair (HRR) pathways 2, 3. Upon detecting DSBs, cells activate the DNA damage response (DDR), a signal-transduction pathway that, among other roles, promotes activation of DNA-damage-dependent checkpoints that slow or halt cell-cycle progression. DSB accrual causes physical discontinuities in the genome and can generate pathogenic mutations and chromosomal rearrangements (deletions, inversions, duplications, or translocations) that are hallmarks of cancer 1. Amongst the various types of DNA lesions that can occur, DNA double-strand breaks (DSBs) are generally considered the most toxic, and can be caused either directly by ionizing radiation (IR) or reactive chemicals, or indirectly via the processing of other types of DNA lesions or breakdown of DNA replication forks. Rapid recognition and accurate repair of DNA damage is crucial for all organisms. Notably, suppressor mutations in ATM-mutant backgrounds are different to those in BRCA1-mutant scenarios, suggesting new opportunities for patient stratification and additional therapeutic vulnerabilities for clinical exploitation. Preventing DSB ligation by NHEJ, or enhancing homologous recombination by BRCA1-A complex disruption, suppresses this toxicity, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions.
We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib reflects delayed engagement of homologous recombination at DNA-replication-fork associated single-ended double-strand breaks (DSBs), allowing some to be subject to toxic NHEJ. Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase I inhibitor topotecan.
Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. Nature Communications volume 10, Article number: 87 ( 2019) ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
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