WD40-repeat protein WDR18 collaborates with TopBP1 to facilitate DNA damage checkpoint signaling.
WD40-repeat protein WDR18 collaborates with TopBP1 to facilitate DNA damage checkpoint signaling.
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DOI：
10.1016/j.bbrc.2012.12.144
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发表时间：
2013-02-15
影响因子：
3.1
通讯作者：
Willis, Jeremy
中科院分区：
文献类型：
--
作者：
Yan, Shan;Willis, Jeremy
所有生物体的基因组都暴露在各种各样的伤害中。为了保持基因组的完整性，真核生物已经进化出一种复杂的监视机制- DNA损伤检查点信号-来检测受损的DNA并阻止细胞周期进程，从而有时间处理和修复DNA损伤。TopBP 1在DNA损伤检查点信号传导的调节中发挥多种作用。然而，TopBP 1如何调节ATR介导的Chk 1磷酸化的分子机制知之甚少。在本通讯中，我们证明了（1）TopBP 1的Chk 1激活结构域在响应几种不同类型的DNA损伤中是至关重要的;（2）WD 40重复蛋白WDR 18在体外和体内与TopBP 1的C-末端缔合;（3）WDR 18与TopBP 1之间的缔合是AT 70诱导的Chk 1磷酸化所必需的;（4）并且WDR 18本身是AT 70触发的Chk 1磷酸化所必需的。此外，WDR 18在体外与Chk 1缔合。这些数据表明，WDR 18通过与TopBP 1和Chk 1的C末端相互作用促进ATR依赖性Chk 1磷酸化。我们的研究结果表明，WDR 18是一个真正的检查点蛋白，WDR 18与TopBP 1一起促进DNA损伤检查点信号传导。
The genomes of all living organisms are exposed to a wide spectrum of insults. To maintain genomic integrity, eukaryotes have evolved an elaborate surveillance mechanism - DNA damage checkpoint signaling - to detect damaged DNA and to arrest cell cycle progression, allowing time to process and repair DNA damage. TopBP1 plays multiple roles in the regulation of DNA damage checkpoint signaling. However, the molecular mechanism of how TopBP1 regulates ATR-mediated Chk1 phosphorylation is poorly understood. In this communication, we demonstrate (1) that the Chk1 activation domain of TopBP1 is critical in response to several different types of DNA damage; (2) that WD40-repeat protein WDR18 associates with the C-terminus of TopBP1 in vitro and in vivo; (3) that the association between WDR18 and TopBP1 is required for AT70-induced Chk1 phosphorylation; (4) and that WDR18 itself is required for AT70-triggered Chk1 phosphorylation. In addition, WDR18 associates with Chk1 in vitro. These data suggest that WDR18 facilitates ATR-dependent Chk1 phosphorylation via interacting with both C-terminus of TopBP1 and Chk1. Our findings indicate that WDR18 is a bona fide checkpoint protein and that WDR18 works together with TopBP1 to promote DNA damage checkpoint signaling.
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