MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways
MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways
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DOI：
10.1038/nature01447
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发表时间：
2003-02-27
期刊：
影响因子：
64.8
通讯作者：
Chen, JJ
中科院分区：
文献类型：
--
作者：
Lou, ZK;Minter-Dykhouse, K;Chen, JJ
叉头同源相关 (FHA) 结构域充当识别磷酸化丝氨酸/苏氨酸基序的蛋白质-蛋白质模块 (1-5)。 FHA 结构域和磷酸化蛋白之间的相互作用被认为在 DNA 损伤信号的转导中具有重要作用；然而，目前尚不清楚含 FHA 结构域的蛋白质如何参与哺乳动物 DNA 损伤反应。在这里，我们报道了一种含有 FHA 结构域的蛋白质——DNA 损伤检查点蛋白 1（MDC1；以前称为 KIAA0170）的蛋白——参与 DNA 损伤反应。 MDC1 定位于 DNA 断裂位点，并在 DNA 损伤后与 CHK2 结合。这种关联由 MDC1 FHA 结构域和 CHK2 的磷酸化 Thr 68 介导。此外，DNA损伤后MDC1以ATM/CHK2依赖性方式磷酸化，表明MDC1可能在ATM-CHK2途径中发挥作用。与这一假设一致，抑制 MDC1 表达会导致 S 期检查点缺陷，并减少响应 DNA 损伤的细胞凋亡，这可以通过野生型 MDC1 的表达来恢复，但不能通过删除 FHA 结构域的 MDC1 来恢复。抑制 MDC1 表达会导致 p53 对 DNA 损伤的稳定性降低。这些结果表明 MDC1 通过其 FHA 结构域被招募到激活的 CHK2 上，并在 CHK2 介导的 DNA 损伤反应中发挥关键作用。
Forkhead-homology-associated (FHA) domains function as protein-protein modules that recognize phosphorylated serine/threonine motifs(1-5). Interactions between FHA domains and phosphorylated proteins are thought to have essential roles in the transduction of DNA damage signals; however, it is unclear how FHA-domain-containing proteins participate in mammalian DNA damage responses. Here we report that a FHA-domain-containing protein-mediator of DNA damage checkpoint protein 1 (MDC1; previously known as KIAA0170)-is involved in DNA damage responses. MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression results in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which can be restored by the expression of wildtype MDC1 but not MDC1 with a deleted FHA domain. Suppression of MDC1 expression results in decreased p53 stabilization in response to DNA damage. These results suggest that MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses.