Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway
Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway
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DOI：
10.1128/mcb.24.22.10016-10025.2004
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发表时间：
2004-11-01
影响因子：
5.3
通讯作者：
Sugimoto, K
中科院分区：
文献类型：
--
作者：
Nakada, D;Hirano, Y;Sugimoto, K
大蛋白激酶，共济失调-毛细血管扩张突变（ATM）和ATM-Rad 3相关（ATR），协调DNA损伤检查点途径。在芽殖酵母中，ATM和ATR同源物分别由TEL 1和MEC 1编码。Mre 11复合物由两种高度相关的蛋白质Mre 11和Rad 50以及第三种蛋白质Xrs 2（芽殖酵母中）或Nbs 1（哺乳动物中）组成。Mre 11复合物控制ATM/Tel 1信号通路以响应双链断裂（DSB）诱导。我们在这里表明，Mre 11复合物的功能与核酸外切酶1（exo 1）在激活的Mec 1信号通路后，DNA损伤和复制块。Mec 1控制UV照射以及DSB诱导后的检查点反应。相应地，Mre 11复合物和Exo 1在DSB和UV诱导的检查点的激活中起重叠作用。Mre 11复合物和Exo 1在DSB末端协同产生长单链DNA（ssDNA）尾，并促进Mec 1与DSB的结合。Ddc 1-Mec 3-Rad 17复合物与DNA损伤位点相关并调节Mec 1信号通路。然而，Ddc 1与DSB的结合不需要Mre 11复合物和Exo 1的功能。Mec 1也控制着对停滞的DNA复制的检查点反应。因此，Mre 11复合物和Exo 1有助于激活复制检查点途径。我们的结果提供了一个模型，其中Mre 11复合物和Exo 1合作产生长ssDNA片段，从而促进Mec 1与DNA损伤或复制阻滞位点的结合。
The large protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), orchestrate DNA damage checkpoint pathways. In budding yeast, ATM and ATR homologs are encoded by TEL1 and MEC1, respectively. The Mre11 complex consists of two highly related proteins, Mre11 and Rad50, and a third protein, Xrs2 in budding yeast or Nbs1 in mammals. The Mre11 complex controls the ATM/Tel1 signaling pathway in response to double-strand break (DSB) induction. We show here that the Mre11 complex functions together with exonuclease 1 (Exo1) in activation of the Mec1 signaling pathway after DNA damage and replication block. Mec1 controls the checkpoint responses following UV irradiation as well as DSB induction. Correspondingly, the Mre11 complex and Exo1 play an overlapping role in activation of DSB- and UV-induced checkpoints. The Mre11 complex and Exo1 collaborate in producing long single-stranded DNA (ssDNA) tails at DSB ends and promote Mec1 association with the DSBs. The Ddc1-Mec3-Rad17 complex associates with sites of DNA damage and modulates the Mec1 signaling pathway. However, Ddc1 association with DSBs does not require the function of the Mre11 complex and Exo1. Mec1 controls checkpoint responses to stalled DNA replication as well. Accordingly, the Mre11 complex and Exo1 contribute to activation of the replication checkpoint pathway. Our results provide a model in which the Mre11 complex and Exo1 cooperate in generating long ssDNA tracts and thereby facilitate Mec1 association with sites of DNA damage or replication block.