| Literature DB >> 34108240 |
Yang Liu1,2, Lu Wang1,2, Xin Xu1,2, Yue Yuan1,2, Bo Zhang1,2, Zeyang Li2, Yuchen Xie1,2, Rui Yan1,2, Zeqi Zheng1,2, Jianguo Ji2, Johanne M Murray3, Antony M Carr3, Daochun Kong4,2.
Abstract
DNA 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.Entities:
Keywords: CMG complex; checkpoint; replication fork stability
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Year: 2021 PMID： 34108240 PMCID： PMC8214678 DOI： 10.1073/pnas.2019183118
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205