Multiple roles for MRE11 at uncapped telomeres.
Multiple roles for MRE11 at uncapped telomeres.
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DOI：
10.1038/nature08196
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发表时间：
2009-08-13
期刊：
影响因子：
64.8
通讯作者：
Chang S
中科院分区：
文献类型：
--
作者：
Deng Y;Guo X;Ferguson DO;Chang S
进行性端粒磨损或shelterin复合物脱帽导致DNA损伤反应（DDR），这是由于细胞无法区分功能失调的端粒末端与DNA双链断裂（DSB）。端粒去保护激活共济失调毛细血管扩张突变（ATM）和毛细血管扩张和Rad 3相关（ATR）激酶依赖性DDR途径，并促进功能失调端粒的有效非同源末端连接（NHEJ）。哺乳动物Mre 11-Rad 50-NBS 1（MRN）复合物与ATM相互作用，以检测染色体DSB并协调全局DNA损伤反应。虽然MRN复合物在功能失调的端粒处积累，但尚不清楚哺乳动物MRN是否促进这些位点的修复。在这里，我们解决这个问题，利用小鼠的等位基因，要么是整个MRN复合物或消除只有核酸酶活性的Mre 11。当端粒重复序列结合因子2（TRF 2）从端粒中去除时，缺乏MRN的细胞不会激活ATM，并且连接酶4（Lig 4）依赖的染色体端到端融合显着减少。残留的染色单体融合只涉及由前导链合成产生的端粒。引人注目的是，虽然缺乏Mre 11核酸酶活性的细胞有效地激活ATM并将53 BP 1募集到脱保护的端粒，但3'端粒突出端持续存在以防止NHEJ介导的染色体融合。在Mre 11核酸酶缺乏的情况下，去除保护3'突出端的shelterin蛋白恢复Lig 4依赖性染色体融合。我们的数据表明，MRN复合物在检测功能失调的端粒中起着关键作用，需要Mre 11核酸酶活性来去除3'端端粒突出端以促进染色体融合。Mre 11也需要保护新复制的前导链端粒不参与NHEJ途径，可能是通过促进5'链切除产生Pot 1a-TPP 1结合的3'突出端，防止NHEJ。
Progressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response (DDR) as a result of a cell’s inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks (DSBs). Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase dependent DDR pathways and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres. The mammalian Mre11-Rad50-NBS1 (MRN) complex interacts with ATM to sense chromosomal DSBs and coordinate global DNA damage responses. While the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by utilizing mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of Mre11. Cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and Ligase 4 (Lig4) dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Strikingly, while cells deficient for Mre11 nuclease activity efficiently activate ATM and recruit 53BP1 to deprotected telomeres, the 3’ telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3’ overhang in the setting of Mre11 nuclease deficiency restores Lig4 dependent chromosome fusions. Our data suggest a critical role for the MRN complex in sensing dysfunctional telomeres, with Mre11 nuclease activity required to remove the 3’ telomeric overhang to promote chromosome fusion. Mre11 is also required to protect newly replicated leading strand telomeres from engaging the NHEJ pathway, likely by promoting 5’ strand resection to generate Pot1a-TPP1 bound 3’ overhangs that prevents NHEJ.
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