Human CDK18 promotes replication stress signaling and genome stability.
Human CDK18 promotes replication stress signaling and genome stability.
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DOI：
10.1093/nar/gkw615
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发表时间：
2016-10-14
影响因子：
14.9
通讯作者：
Collis SJ
中科院分区：
文献类型：
--
作者：
Barone G;Staples CJ;Ganesh A;Patterson KW;Bryne DP;Myers KN;Patil AA;Eyers CE;Maslen S;Skehel JM;Eyers PA;Collis SJ
细胞周期蛋白依赖性激酶（CDK）协调细胞周期检查点与DNA修复机制，共同维持基因组稳定性。然而，可能导致基因组不稳定性的无数机制仍有待充分阐明。在这里，我们确定CDK18（PCTAIRE 3）作为一种新的基因组稳定性调节因子，并表明CDK18的耗竭会导致内源性DNA损伤和染色体异常的增加。CDK18耗尽的细胞在早期S期积累，表现出延迟的复制叉动力学和减少的ATR激酶信号传导响应复制应激。在机制上，CDK18与RAD 9、RAD 17和TOPBP1相互作用，并且CDK18缺陷导致响应于复制应激的RAD 17和RAD 9染色质保留减少。重要的是，我们证明了这些表型被外源性CDK18以激酶依赖性方式拯救。总的来说，这些数据揭示了CDK18在复制应激信号传导中的限速作用，并将其确立为基因组完整性的新型调节剂。
Cyclin-dependent kinases (CDKs) coordinate cell cycle checkpoints with DNA repair mechanisms that together maintain genome stability. However, the myriad mechanisms that can give rise to genome instability are still to be fully elucidated. Here, we identify CDK18 (PCTAIRE 3) as a novel regulator of genome stability, and show that depletion of CDK18 causes an increase in endogenous DNA damage and chromosomal abnormalities. CDK18-depleted cells accumulate in early S-phase, exhibiting retarded replication fork kinetics and reduced ATR kinase signaling in response to replication stress. Mechanistically, CDK18 interacts with RAD9, RAD17 and TOPBP1, and CDK18-deficiency results in a decrease in both RAD17 and RAD9 chromatin retention in response to replication stress. Importantly, we demonstrate that these phenotypes are rescued by exogenous CDK18 in a kinase-dependent manner. Collectively, these data reveal a rate-limiting role for CDK18 in replication stress signalling and establish it as a novel regulator of genome integrity.
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影响因子：
8
作者：
Barette, C;Jariel-Encontre, I;Piette, J
通讯作者：
Piette, J
影响因子：
4.8
作者：
Lee, Joon;Kumagai, Akiko;Dunphy, William G.
通讯作者：
Dunphy, William G.
DOI：
10.1073/pnas.0437927100
发表时间：
2003-02-18
影响因子：
11.1
作者：
Bermudez, VP;Lindsey-Boltz, LA;Sancar, A
通讯作者：
Sancar, A
影响因子：
10.5
作者：
Blazek, Dalibor;Kohoutek, Jiri;Peterlin, B. Matija
通讯作者：
Peterlin, B. Matija
影响因子：
--
作者：
Cole, Adam R.
通讯作者：
Cole, Adam R.