DNA-PKcs promotes fork reversal and chemoresistance

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 promo...

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Bibliographic Details
Published in:Molecular cell Vol. 82; no. 20; p. 3932
Main Authors: Dibitetto, Diego, Marshall, Shannon, Sanchi, Andrea, Liptay, Martin, Badar, Jumana, Lopes, Massimo, Rottenberg, Sven, Smolka, Marcus B
Format: Journal Article
Language:English
Published: United States 20.10.2022
Subjects:
DNA - genetics
DNA Breaks, Double-Stranded
DNA Damage
DNA End-Joining Repair
DNA Repair
DNA Replication
Drug Resistance, Neoplasm - genetics
DNA-PKcs
DNA replication
chemoresistance
fork reversal
PARP inhibitor
BRCA1
NHEJ
BRCA2
ISSN:1097-4164, 1097-4164
Online Access:Get more information
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Summary: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.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2022.08.028