Chk1 phosphorylation of Metnase enhances DNA repair but inhibits replication fork restart.
Chk1 phosphorylation of Metnase enhances DNA repair but inhibits replication fork restart.
复制标题
DOI：
10.1038/onc.2011.586
复制
发表时间：
2012-09-20
期刊：
影响因子：
8
通讯作者：
Lee SH
中科院分区：
文献类型：
--
作者：
Hromas R;Williamson EA;Fnu S;Lee YJ;Park SJ;Beck BD;You JS;Leitao A;Nickoloff JA;Lee SH
Chk 1通过下游效应物的磷酸化既阻止复制叉又增强DNA损伤的修复。虽然在确定Chk 1活性的效应物方面已经做出了杰出的努力，但其活性的机制仍有待确定。Metnase/SETMAR是SET和转座酶结构域蛋白，其促进DNA双链断裂（DSB）修复和停滞的复制叉的重新启动。在这项研究中，我们发现Metnase在体内仅在Ser 495（S495）上磷酸化，以响应电离辐射引起的DNA损伤。Chk 1是这种磷酸化事件的主要介质。我们先前已经表明，野生型（wt）Metnase与工程化细胞系统中人工诱导的DSB附近的染色质缔合。然而，S495 A Metnase突变体不能被Chk 1磷酸化，其DSB染色质缔合有缺陷。当与野生型（wt）Metnase相比时，S495 A突变体也不能支持诱导的DSB的修复。有趣的是，与wt Metnase相比，S495 A突变体表现出停滞的复制叉的增加的重新启动。因此，Metnase的S495磷酸化在其两个主要功能之间存在差异，即增强DSB修复和抑制复制叉重启。总之，这些数据有助于深入了解Chk 1增强DNA损伤修复的机制，同时抑制停滞的复制叉重新启动。
Chk1 both arrests replication forks and enhances repair of DNA damage by phosphorylation of downstream effectors. While there has been a distinguished effort in identifying effectors of Chk1 activity, there are still mechanisms of its activities that are yet to be identified. Metnase/SETMAR is a SET and transposase domain protein that promotes both DNA double strand break (DSB) repair and re-start of stalled replication forks. In this study, we show that Metnase is phosphorylated only on Ser495 (S495) in vivo in response to DNA damage by ionizing radiation. Chk1 is the major mediator of this phosphorylation event. We had previously shown that wild type (wt) Metnase associates with chromatin near an artificially induced DSB in an engineered cell system. However, an S495A Metnase mutant, which could not be phosphorylated by Chk1, had a defect in its DSB chromatin association. The S495A mutant also failed to support repair of an induced DSB when compared with wild type (wt) Metnase. Interestingly, the S495A mutant demonstrated increased restart of stalled replication forks compared to wt Metnase. Thus, S495 phosphorylation of Metnase differentiates between its two main functions, enhancing DSB repair and repressing replication fork restart. In summary, these data lend insight into the mechanism by which Chk1 enhances repair of DNA damage while at the same time repressing stalled replication fork restart.
登录
查看更多内容
DOI：
10.2741/3385
发表时间：
2009-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Reyland ME
通讯作者：
Reyland ME
影响因子：
4.7
作者：
Lee, YJ;Park, SJ;Lee, SH
通讯作者：
Lee, SH
影响因子：
6.4
作者：
Firulli, Beth A.;Virshup, David M.;Firulli, Anthony B.
通讯作者：
Firulli, Anthony B.
影响因子：
7.8
作者：
Kim, Jong-Soo;Krasieva, Tatiana B;Kurumizaka, Hitoshi;Chen, David J;Taylor, A Malcolm R;Yokomori, Kyoko
通讯作者：
Yokomori, Kyoko
影响因子：
5.3
作者：
Leung-Pineda, Van;Ryan, Christine E.;Piwnica-Worms, Helen
通讯作者：
Piwnica-Worms, Helen