ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.
Animals
Antineoplastic Agents
/ pharmacology
Ataxia Telangiectasia Mutated Proteins
/ genetics
BRCA1 Protein
/ metabolism
CRISPR-Cas Systems
/ genetics
Cell Line, Tumor
Cell Survival
/ genetics
DNA Breaks, Double-Stranded
/ drug effects
DNA End-Joining Repair
/ genetics
DNA Ligase ATP
/ metabolism
DNA Replication
/ drug effects
Drug Resistance, Neoplasm
/ genetics
Female
Humans
Mice
Mice, Inbred NOD
Mice, Knockout
Mouse Embryonic Stem Cells
Mutation
Neoplasms, Experimental
/ drug therapy
Phthalazines
/ pharmacology
Piperazines
/ pharmacology
Topotecan
/ pharmacology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 01 2019
08 01 2019
Historique:
received:
14
08
2018
accepted:
15
11
2018
entrez:
10
1
2019
pubmed:
10
1
2019
medline:
21
3
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30622252
doi: 10.1038/s41467-018-07729-2
pii: 10.1038/s41467-018-07729-2
pmc: PMC6325118
doi:
Substances chimiques
Antineoplastic Agents
0
BRCA1 Protein
0
LIG4 protein, human
0
Phthalazines
0
Piperazines
0
Topotecan
7M7YKX2N15
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Atm protein, mouse
EC 2.7.11.1
DNA Ligase ATP
EC 6.5.1.1
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
87Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 11224
Pays : United Kingdom
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