Nonenzymatic role for WRN in preserving nascent DNA strands after replication stress.
Nonenzymatic role for WRN in preserving nascent DNA strands after replication stress.
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DOI：
10.1016/j.celrep.2014.10.025
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发表时间：
2014-11-20
期刊：
影响因子：
8.8
通讯作者：
Asaithamby A
中科院分区：
文献类型：
--
作者：
Su F;Mukherjee S;Yang Y;Mori E;Bhattacharya S;Kobayashi J;Yannone SM;Chen DJ;Asaithamby A
WRN是Werner综合征（WS）中的缺陷蛋白，是一种多功能核酸酶，参与DNA损伤修复、复制和基因组稳定性维持。据推测，WRN的核酸酶活性对于这些功能是至关重要的。在这里，我们报告一个非酶的作用WRN在保存新生的DNA链复制应力。我们发现WRN的缺乏导致复制应激后新生DNA链的缩短。此外，我们发现MRE 11的外切核酸酶活性负责在WRN不存在的情况下缩短新复制的DNA。从机制上讲，NBS 1的N-末端FHA结构域将WRN招募到复制相关的DNA双链断裂中，以稳定Rad 51并限制其C-末端结合伴侣MRE 11的核酸酶活性。因此，以前未被认识到的非酶的功能WRN在新生的DNA链的稳定揭示了WS个体的基因组不稳定性的起源的分子原因。
WRN, the protein defective in Werner Syndrome (WS), is a multifunctional nuclease involved in DNA damage repair, replication and genome stability maintenance. It was assumed that the nuclease activities of WRN were critical for these functions. Here, we report a non-enzymatic role for WRN in preserving nascent DNA strands following replication stress. We found that lack of WRN led to shortening of nascent DNA strands after replication stress. Further, we discovered that the exonuclease activity of MRE11 was responsible for the shortening of newly replicated DNA in the absence of WRN. Mechanistically, the N-terminal FHA domain of NBS1 recruits WRN to replication-associated DNA double-stranded breaks to stabilize Rad51 and to limit the nuclease activity of its C-terminal binding partner MRE11. Thus, the previously unrecognized non-enzymatic function of WRN in the stabilization of nascent DNA strands sheds light on the molecular reason for the origin of genome instability in WS individuals.