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首页> 外文期刊>Cell cycle >MCL-1 localizes to sites of DNA damage and regulates DNA damage response.
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MCL-1 localizes to sites of DNA damage and regulates DNA damage response.

机译：MCL-1定位于DNA损伤位点并调节DNA损伤反应。

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摘要

MCL-1, a pro-survival member of the BCL-2 family, was previously shown to have functions in ATR-dependent Chk1 phosphorylation following DNA damage. To further delineate these functions, we explored possible differences in DNA damage response caused by lack of MCL-1 in mouse embryo fibroblasts (MEFs). As expected, Mcl-1(-/-) MEFs had delayed Chk1 phosphorylation following etoposide treatment, compared to wild type MEFs. However, their response to hydroxyurea, which causes a G(1)/S checkpoint response, was not significantly different. In addition, appearance of gamma-H2AX was delayed in the Mcl-1(-/-) MEFs treated with etoposide. We next investigated whether MCL-1 is present, together with other DNA damage response proteins, at the sites of DNA damage. Immunoprecipitation of etoposide-treated extracts with anti-MCL-1 antibody showed association of MCL-1 with gamma-H2AX as well as NBS1. Immunofluorescent staining for MCL-1 further showed increased co-staining of MCL-1 and NBS1 following DNA damage. By using a system that creates DNA double strand breaks at specific sites in the genome, we demonstrated that MCL-1 is recruited directly adjacent to the sites of damage. Finally, in a direct demonstration of the importance of MCL-1 in allowing proper repair of DNA damage, we found that treatment for two brief exposures to etoposide , followed by periods of recovery, which mimics the clinical situation of etoposide use, resulted in greater accumulation of chromosomal abnormalities in the MEFs that lacked MCL-1. Together, these data indicate an important role for MCL-1 in coordinating DNA damage mediated checkpoint response, and have broad implications for the importance of MCL-1 in maintenance of genome integrity.
机译：MCL-1，BCL-2家族的一个幸存成员，以前被证明在DNA损伤后在ATR依赖性Chk1磷酸化中具有功能。为了进一步描述这些功能，我们探索了小鼠胚胎成纤维细胞（MEF）中缺少MCL-1引起的DNA损伤反应的可能差异。正如预期的那样，与野生型MEF相比，依托泊苷治疗后Mcl-1（-/-）MEF延迟了Chk1磷酸化。但是，他们对引起G（1）/ S检查点响应的羟基脲的反应没有显着差异。另外，在依托泊苷处理的Mcl-1（-/-）MEF中，γ-H2AX的出现被延迟。接下来，我们调查了DNA损伤部位是否存在MCL-1，以及其他DNA损伤应答蛋白。依托泊苷处理的提取物与抗MCL-1抗体的免疫沉淀显示MCL-1与γ-H2AX和NBS1相关。 MCL-1的免疫荧光染色进一步显示，DNA损伤后，MCL-1和NBS1的共染色增加。通过使用在基因组中特定位点产生DNA双链断裂的系统，我们证明了MCL-1被直接募集到受损位点附近。最后，在直接证实MCL-1在适当修复DNA损伤中的重要性方面，我们发现两次短暂暴露于依托泊苷的治疗，随后是恢复期，模仿了依托泊苷的临床使用情况，其结果是缺乏MCL-1的MEF中染色体异常的积累。总之，这些数据表明MCL-1在协调DNA损伤介导的检查点反应中的重要作用，并对MCL-1在维持基因组完整性中的重要性具有广泛的意义。

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