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The intra-S phase checkpoint directly regulates replication elongation to preserve the integrity of stalled replisomes
journal contribution
posted on 2023-06-10, 00:05 authored by Yang Liu, Lu Wang, Xin Xu, Yue Yuan, Bo Zhang, Zeyang Li, Yuchen Xie, Rui Yan, Zeqi Zheng, Jianguo Ji, Jo Murray, Antony CarrAntony Carr, Daochun KongDNA replication is dramatically slowed down under replication stress. The regulation of replication speed is a conserved response in eukaryotes and, in fission yeast, requires the checkpoint kinases Rad3ATR and Cds1Chk2 However, the underlying mechanism of this checkpoint regulation remains unresolved. Here, we report that the Rad3ATR-Cds1Chk2 checkpoint directly targets the Cdc45-MCM-GINS (CMG) replicative helicase under replication stress. When replication forks stall, the Cds1Chk2 kinase directly phosphorylates Cdc45 on the S275, S322, and S397 residues, which significantly reduces CMG helicase activity. Furthermore, in cds1 Chk2 -mutated cells, the CMG helicase and DNA polymerases are physically separated, potentially disrupting replisomes and collapsing replication forks. This study demonstrates that the intra-S phase checkpoint directly regulates replication elongation, reduces CMG helicase processivity, prevents CMG helicase delinking from DNA polymerases, and therefore helps preserve the integrity of stalled replisomes and replication forks.
Funding
Replication fork stability and fork restart; G0745; MRC-MEDICAL RESEARCH COUNCIL; G1100074-E01/1
History
Publication status
- Published
File Version
- Accepted version
Journal
Proceedings of the National Academy of Sciences (PNAS)ISSN
0027-8424Publisher
National Academy of SciencesExternal DOI
Issue
24Volume
118Article number
a2019183118Event location
United StatesDepartment affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-06-14First Open Access (FOA) Date
2021-06-14First Compliant Deposit (FCD) Date
2021-06-14Usage metrics
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