Intrinsic ATR signaling shapes DNA end resection and suppresses toxic DNA-PKcs signaling.
Journal
NAR cancer
ISSN: 2632-8674
Titre abrégé: NAR Cancer
Pays: England
ID NLM: 101769553
Informations de publication
Date de publication:
Jun 2020
Jun 2020
Historique:
received:
31
03
2020
revised:
08
04
2020
accepted:
16
04
2020
entrez:
4
8
2020
pubmed:
4
8
2020
medline:
4
8
2020
Statut:
ppublish
Résumé
Most cancer cells experience oncogene-induced replication stress and, as a result, exhibit high intrinsic activation of the ATR kinase. Although cancer cells often become more dependent on ATR for survival, the precise mechanism by which ATR signaling ensures cancer cell fitness and viability remains incompletely understood. Here, we find that intrinsic ATR signaling is crucial for the ability of cancer cells to promote DNA end resection, the first step in homology-directed DNA repair. Inhibition of ATR over multiple cell division cycles depletes the pool of pro-resection factors and prevents the engagement of RAD51 as well as RAD52 at nuclear foci, leading to toxic DNA-PKcs signaling and hypersensitivity to PARP inhibitors. The effect is markedly distinct from acute ATR inhibition, which blocks RAD51-mediated repair but not resection and engagement of RAD52. Our findings reveal a key pro-resection function for ATR and define how ATR inhibitors can be used for effective manipulation of DNA end resection capacity and DNA repair outcomes in cancer cells.
Identifiants
pubmed: 32743550
doi: 10.1093/narcan/zcaa006
pii: zcaa006
pmc: PMC7380482
doi:
Types de publication
Journal Article
Langues
eng
Pagination
zcaa006Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM097272
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM141159
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of NAR Cancer.
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