van den Bosch Michael, Bree Ronan T, Lowndes Noel F
Genome Stability Laboratory, Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland-Galway, University Road, Galway, Ireland.
EMBO Rep. 2003 Sep;4(9):844-9. doi: 10.1038/sj.embor.embor925.
The MRE11-RAD50-NBS1 (MRN) protein complex has been linked to many DNA metabolic events that involve DNA double-stranded breaks (DSBs). In vertebrate cells, all three components are encoded by essential genes, and hypomorphic mutations in any of the human genes can result in genome-instability syndromes. MRN is one of the first factors to be localized to the DNA lesion, where it might initially have a structural role by tethering together, and therefore stabilizing, broken chromosomes. This suggests that MRN could function as a lesion-specific sensor. As well as binding to DNA, MRN has other roles in both the processing and assembly of large macromolecular complexes (known as foci) that facilitate efficient DSB responses. Recently, a novel mediator protein, mediator of DNA damage checkpoint protein 1 (MDC1), was shown to co-immunoprecipitate with the MRN complex and regulate MRE11 foci formation. However, whether the initial recruitment of MRN to DSBs requires MDC1 is unclear. Here, we focus on recent developments in MRN research and propose a model for how DSBs are sensed and the cellular responses to them are mediated.
MRE11-RAD50-NBS1（MRN）蛋白复合物与许多涉及DNA双链断裂（DSB）的DNA代谢事件相关联。在脊椎动物细胞中，所有这三个组分均由必需基因编码，并且任何一个人类基因中的亚效突变都可能导致基因组不稳定综合征。MRN是最早定位于DNA损伤部位的因子之一，在那里它可能最初通过将断裂的染色体拴在一起并使其稳定而发挥结构作用。这表明MRN可能作为损伤特异性传感器发挥作用。除了与DNA结合外，MRN在促进有效DSB反应的大型大分子复合物（称为病灶）的加工和组装中也具有其他作用。最近，一种新型的介导蛋白，即DNA损伤检查点蛋白1（MDC1）的介导蛋白，被证明与MRN复合物共免疫沉淀并调节MRE11病灶的形成。然而，MRN最初募集到DSB是否需要MDC1尚不清楚。在这里，我们关注MRN研究的最新进展，并提出一个关于如何感知DSB以及介导细胞对它们的反应的模型。
