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ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
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ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
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Journal Article
ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
2019
Overview
Mutations in the
ATM
tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase I inhibitor topotecan. 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. 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. 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. 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.
Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. Here, the authors provide evidence that these hypersensitivities reflect a crucial role for ATM at damaged replication forks being to prevent toxic DNA end-joining leading to chromosome fusions and cell death.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 14
/ 49
/ 631/208
/ 631/67
/ 631/80
/ 82/58
/ Animals
/ Antineoplastic Agents - pharmacology
/ Antineoplastic Agents - therapeutic use
/ Ataxia Telangiectasia Mutated Proteins - genetics
/ Ataxia Telangiectasia Mutated Proteins - metabolism
/ CRISPR
/ CRISPR-Cas Systems - genetics
/ Damage
/ DNA
/ DNA Breaks, Double-Stranded - drug effects
/ DNA End-Joining Repair - genetics
/ DNA Replication - drug effects
/ Drug Resistance, Neoplasm - genetics
/ Female
/ Genomes
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Mutation
/ Neoplasms, Experimental - drug therapy
/ Neoplasms, Experimental - genetics
/ Neoplasms, Experimental - pathology
/ Phthalazines - therapeutic use
/ Piperazines - therapeutic use
/ Ribose
/ Science
/ Screens
/ Toxicity
