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首页> 外文期刊>Cell cycle >ATM regulates Mre11-dependent DNA end-degradation and microhomology-mediated end joining.
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ATM regulates Mre11-dependent DNA end-degradation and microhomology-mediated end joining.

机译：ATM调节Mre11依赖性DNA末端降解和微同源性介导的末端连接。

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The human disorder ataxia telangiectasia (AT), which is characterized by genetic instability and neurodegeneration, results from mutation of the ataxia telangiectasia mutated (ATM) kinase. The loss of ATM leads to cell cycle checkpoint deficiencies and other DNA damage signaling defects that do not fully explain all pathologies associated with A-T including neuronal loss. In addressing this enigma, we find here that ATM suppresses DNA double-strand break (DSB) repair by microhomology-mediated end joining (MMEJ). We show that ATM repression of DNA end-degradation is dependent on its kinase activities and that Mre11 is the major nuclease behind increased DNA end-degradation and MMEJ repair in A-T. Assessment of MMEJ by an in vivo reporter assay system reveals decreased levels of MMEJ repair in Mre11-knockdown cells and in cells treated with Mre11-nuclease inhibitor mirin. Structure-based modeling of Mre11 dimer engaging DNA ends suggests the 5' ends of a bridged DSB are juxtaposed such that DNA unwinding and 3'-5' exonuclease activities may collaborate to facilitate simultaneous pairing of extended 5' termini and exonucleolytic degradation of the 3' ends in MMEJ. Together our results provide an integrated understanding of ATM and Mre11 in MMEJ: ATM has a critical regulatory function in controlling DNA end-stability and error-prone DSB repair and Mre11 nuclease plays a major role in initiating MMEJ in mammalian cells. These functions of ATM and Mre11 could be particularly important in neuronal cells, which are post-mitotic and therefore depend on mechanisms other than homologous recombination between sister chromatids to repair DSBs.
机译：共济失调毛细血管扩张症（AT）的特征是遗传不稳定性和神经退行性变，其原因是共济失调毛细血管扩张症（ATM）激酶发生突变。 ATM的丢失会导致细胞周期检查点缺陷和其他DNA损伤信号缺陷，这些缺陷不能完全解释与A-T相关的所有病理，包括神经元丢失。在解决这个难题时，我们在这里发现ATM通过微同源介导的末端连接（MMEJ）抑制DNA双链断裂（DSB）修复。我们表明，ATM抑制DNA末端降解取决于其激酶活性，并且Mre11是在A-T中增加DNA末端降解和MMEJ修复的主要核酸酶。通过体内报告基因检测系统评估MMEJ，发现Mre11敲低细胞和Mre11核酸酶抑制剂米林处理过的细胞中MMEJ修复水平降低。 Mre11二聚体参与DNA末端的基于结构的建模表明，桥接的DSB的5'末端并列，从而DNA展开和3'-5'核酸外切酶活性可以协同作用，以促进延长的5'末端同时配对和3的核酸外切降解'以MMEJ结尾。我们的研究结果共同提供了对MMEJ中ATM和Mre11的综合理解：ATM在控制DNA末端稳定性和易错DSB修复中具有关键的调节功能，而Mre11核酸酶在启动哺乳动物细胞中的MMEJ中起主要作用。 ATM和Mre11的这些功能在有丝分裂后的神经元细胞中可能尤其重要，因此，除了姐妹染色单体之间的同源重组以外，还取决于其他机制来修复DSB。

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