MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals
MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals
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DOI：
10.1016/j.molcel.2005.11.025
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发表时间：
2006-01-20
期刊：
影响因子：
16
通讯作者：
Chen, JJ
中科院分区：
文献类型：
--
作者：
Lou, ZK;Minter-Dykhouse, K;Chen, JJ
MDC1在DNA损伤后的检查点激活和DNA修复中起作用。为了解决MDC1的生理作用，我们破坏了小鼠的MDC1基因。MDC1（-/-）小鼠再现了H2AX（-/-）小鼠的许多表型，包括生长迟缓、雄性不育、免疫缺陷、染色体不稳定、DNA修复缺陷和辐射敏感性。在分子水平上，H2AX、MDC1和ATM形成一个正反馈回路，MDC1直接介导H2AX与ATM的相互作用。MDC1通过其BRCT结构域结合磷酸化的H2AX，通过其FHA结构域结合ATM。通过这些相互作用，MDC1在DNA损伤位点两侧积累活化的ATM，促进H2AX进一步依赖ATM的磷酸化和DNA损伤信号的扩增。在缺少MDC1的情况下，许多下游ATM信令事件是有缺陷的。这些结果表明，MDC1作为ATM通路的信号放大器，在控制适当的DNA损伤反应和维持基因组稳定性方面至关重要。
MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1(-/-) mice recapitulated many phenotypes of H2AX(-/-) mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability.