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dc.contributor.author
Ceppi, Ilaria
dc.contributor.author
Cannavo, Elda
dc.contributor.author
Bret, Hélène
dc.contributor.author
Camarillo, Rosa
dc.contributor.author
Vivalda, Francesca
dc.contributor.author
Thakur, Roshan Singh
dc.contributor.author
Romero-Franco, Amador
dc.contributor.author
Sartori, Alessandro A.
dc.contributor.author
Huertas, Pablo
dc.contributor.author
Guérois, Raphaël
dc.contributor.author
Cejka, Petr
dc.date.accessioned
2023-04-20T11:50:17Z
dc.date.available
2023-03-31T03:21:30Z
dc.date.available
2023-03-31T07:53:36Z
dc.date.available
2023-04-20T11:50:17Z
dc.date.issued
2023-02-01
dc.identifier.issn
0890-9369
dc.identifier.issn
1549-5477
dc.identifier.other
10.1101/gad.349981.122
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/605845
dc.identifier.doi
10.3929/ethz-b-000605845
dc.description.abstract
DNA double-strand break (DSB) repair is initiated by DNA end resection. CtIP acts in short-range resection to stimulate MRE11-RAD50-NBS1 (MRN) to endonucleolytically cleave 5'-terminated DNA to bypass protein blocks. CtIP also promotes the DNA2 helicase-nuclease to accelerate long-range resection downstream from MRN. Here, using AlphaFold2, we identified CtIP-F728E-Y736E as a separation-of-function mutant that is still proficient in conjunction with MRN but is not able to stimulate ssDNA degradation by DNA2. Accordingly, CtIP-F728E-Y736E impairs physical interaction with DNA2. Cellular assays revealed that CtIP-F728E-Y736E cells exhibit reduced DSB-dependent chromatin-bound RPA, impaired long-range resection, and increased sensitivity to DSB-inducing drugs. Previously, CtIP was shown to be targeted by PLK1 to inhibit long-range resection, yet the underlying mechanism was unclear. We show that the DNA2-interacting region in CtIP includes the PLK1 target site at S723. The integrity of S723 in CtIP is necessary for the stimulation of DNA2, and phosphorylation of CtIP by PLK1 in vitro is consequently inhibitory, explaining why PLK1 restricts long-range resection. Our data support a model in which CDK-dependent phosphorylation of CtIP activates resection by MRN in S phase, and PLK1-mediated phosphorylation of CtIP disrupts CtIP stimulation of DNA2 to attenuate long-range resection later at G2/M.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Cold Spring Harbor Laboratory Press
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc/4.0/
dc.subject
DNA end resection
en_US
dc.subject
Homologous recombination
en_US
dc.subject
DNA repair
en_US
dc.subject
Phosphorylation
en_US
dc.title
PLK1 regulates CtIP and DNA2 interplay in long-range DNA end resection
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial 4.0 International
dc.date.published
2023-02-06
ethz.journal.title
Genes & Development
ethz.journal.volume
37
en_US
ethz.journal.issue
3-4
en_US
ethz.journal.abbreviated
Genes & Dev
ethz.pages.start
119
en_US
ethz.pages.end
135
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.scopus
ethz.publication.place
Woodbury, NY
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2023-03-31T03:21:30Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2023-03-31T07:53:38Z
ethz.rosetta.lastUpdated
2024-02-02T21:45:44Z
ethz.rosetta.versionExported
true
ethz.COinS
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