DNA-PKcs promotes fork reversal and chemoresistance.
BRCA1
BRCA2
DNA replication
DNA-PKcs
NHEJ
PARP inhibitor
chemoresistance
fork reversal
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
20 10 2022
20 10 2022
Historique:
received:
08
03
2022
revised:
25
06
2022
accepted:
23
08
2022
pubmed:
22
9
2022
medline:
26
10
2022
entrez:
21
9
2022
Statut:
ppublish
Résumé
The DNA-PKcs kinase mediates the repair of DNA double-strand breaks via classical non-homologous end joining (NHEJ). DNA-PKcs is also recruited to active replication forks, although a role for DNA-PKcs in the control of fork dynamics is unclear. Here, we identify a crucial role for DNA-PKcs in promoting fork reversal, a process that stabilizes stressed replication forks and protects genome integrity. DNA-PKcs promotes fork reversal and slowing in response to several replication stress-inducing agents in a manner independent of its role in NHEJ. Cells lacking DNA-PKcs activity show increased DNA damage during S-phase and cellular sensitivity to replication stress. Notably, prevention of fork slowing and reversal via DNA-PKcs inhibition efficiently restores chemotherapy sensitivity in BRCA2-deficient mammary tumors with acquired PARPi resistance. Together, our data uncover a new key regulator of fork reversal and show how DNA-PKcs signaling can be manipulated to alter fork dynamics and drug resistance in cancer.
Identifiants
pubmed: 36130596
pii: S1097-2765(22)00848-6
doi: 10.1016/j.molcel.2022.08.028
pmc: PMC9588680
mid: NIHMS1834570
pii:
doi:
Substances chimiques
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3932-3942.e6Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM097272
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM141159
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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