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MDC1 is a mediator of the mammalian DNA damage checkpoint

机译：MDC1是哺乳动物DNA损伤检查点的介体

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To counteract the continuous exposure of cells to agents that damage DNA, cells have evolved complex regulatory networks called checkpoints to sense DNA damage and coordinate DNA replication, cell-cycle arrest and DNA repair(1). It has recently been shown that the histone H2A variant H2AX specifically controls the recruitment of DNA repair proteins to the sites of DNA damage(2-4). Here we identify a novel BRCA1 carboxy-terminal (BRCT) and forkhead-associated (FHA) domain-containing protein, MDC1 (mediator of DNA damage checkpoint protein 1), which works with H2AX to promote recruitment of repair proteins to the sites of DNA breaks and which, in addition, controls damage-induced cell-cycle arrest checkpoints. MDC1 forms foci that co-localize extensively with gamma-H2AX foci within minutes after exposure to ionizing radiation. H2AX is required for MDC1 foci formation, and MDC1 forms complexes with phosphorylated H2AX. Furthermore, this interaction is phosphorylation dependent as peptides containing the phosphorylated site on H2AX bind MDC1 in a phosphorylation-dependent manner. We have shown by using small interfering RNA (siRNA) that cells lacking MDC1 are sensitive to ionizing radiation, and that MDC1 controls the formation of damage-induced 53BP1, BRCA1 and MRN foci, in part by promoting efficient H2AX phosphorylation. In addition, cells lacking MDC1 also fail to activate the intra-S phase and G2/M phase cell-cycle checkpoints properly after exposure to ionizing radiation, which was associated with an inability to regulate Chk1 properly. These results highlight a crucial role for MDC1 in mediating transduction of the DNA damage signal. [References: 28]
机译：为了抵消细胞对破坏DNA的持续暴露，细胞已经进化出称为检查点的复杂调节网络，以感知DNA损伤并协调DNA复制，细胞周期停滞和DNA修复（1）。最近显示，组蛋白H2A变体H2AX专门控制DNA修复蛋白募集到DNA损伤部位（2-4）。在这里，我们确定了一种新型的BRCA1羧基末端（BRCT）和叉头相关（FHA）域包含蛋白MDC1（DNA损伤检查点蛋白1的介体），该蛋白与H2AX共同促进修复蛋白向DNA部位的募集中断，并控制损伤诱导的细胞周期停滞检查点。 MDC1形成的焦点在暴露于电离辐射后数分钟之内就与γ-H2AX焦点广泛共定位。 MDC1焦点形成需要H2AX，并且MDC1与磷酸化的H2AX形成复合物。此外，这种相互作用是磷酸化依赖性的，因为包含H2AX上磷酸化位点的肽以磷酸化依赖性方式结合MDC1。我们已经通过使用小干扰RNA（siRNA）表明，缺少MDC1的细胞对电离辐射敏感，而MDC1部分地通过促进有效的H2AX磷酸化来控制损伤诱导的53BP1，BRCA1和MRN灶的形成。此外，缺少MDC1的细胞在暴露于电离辐射后也无法正确激活S内和G2 / M期细胞周期检查点，这与无法正确调节Chk1有关。这些结果突出了MDC1在介导DNA损伤信号转导中的关键作用。 [参考：28]

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