当前位置: X-MOL 学术Proc. Natl. Acad. Sci. U.S.A. › 论文详情
The intra-S phase checkpoint directly regulates replication elongation to preserve the integrity of stalled replisomes [Genetics]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-06-15 , DOI: 10.1073/pnas.2019183118
Yang Liu, Lu Wang, Xin Xu, Yue Yuan, Bo Zhang, Zeyang Li, Yuchen Xie, Rui Yan, Zeqi Zheng, Jianguo Ji, Johanne M. Murray, Antony M. Carr, Daochun Kong

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 cds1Chk2-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.



中文翻译:

Intra-S 阶段检查点直接调节复制延伸以保持停滞复制体的完整性 [遗传学]

DNA复制在复制压力下显着减慢。复制速度的调节在真核生物中是一种保守的反应,在裂变酵母中,需要检查点激酶 Rad3 ATR和 Cds1 Chk2。然而,这种检查点调节的潜在机制仍未得到解决。在这里,我们报告 Rad3 ATR -Cds1 Chk2检查点直接针对复制压力下的 Cdc45-MCM-GINS (CMG) 复制解旋酶。当复制叉停止时,Cds1 Chk2激酶直接磷酸化 S275、S322 和 S397 残基上的 Cdc45,从而显着降低 CMG 解旋酶活性。此外,在cds1 Chk2- 突变的细胞,CMG 解旋酶和 DNA 聚合酶在物理上是分开的,可能会破坏复制体和折叠复制叉。这项研究表明,S 内阶段检查点直接调节复制延伸,降低 CMG 解旋酶持续合成能力,防止 CMG 解旋酶与 DNA 聚合酶脱链,因此有助于保持停滞的复制体和复制叉的完整性。

更新日期:2021-06-10
全部期刊列表>>
virulence
欢迎新作者ACS
中国作者高影响力研究精选
虚拟特刊
屿渡论文,编辑服务
浙大
上海中医药大学
深圳大学
上海交通大学
南方科技大学
浙江大学
清华大学
徐晶
张大卫
彭孝军
北京大学
隐藏1h前已浏览文章
课题组网站
新版X-MOL期刊搜索和高级搜索功能介绍
ACS材料视界
华辉
天合科研
x-mol收录
试剂库存
down
wechat
bug