Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
J Cell Biol. 2011 Apr 18;193(2):267-73. doi: 10.1083/jcb.201010026. Epub 2011 Apr 11.
Human TopBP1 is a major player in the control of the DNA replication checkpoint. In this study, we identified MDC1, a key checkpoint protein involved in the cellular response to DNA double-strand breaks, as a TopBP1-associated protein. The specific TopBP1-MDC1 interaction is mediated by the fifth BRCT domain of TopBP1 and the Ser-Asp-Thr (SDT) repeats of MDC1. In addition, we demonstrated that TopBP1 accumulation at stalled replication forks is promoted by the H2AX/MDC1 signaling cascade. Moreover, MDC1 is important for ATR-dependent Chk1 activation in response to replication stress. Collectively, our data suggest that MDC1 facilitates several important steps in both cellular DNA damage response and the DNA replication checkpoint.
人 TopBP1 是控制 DNA 复制检查点的主要参与者。在这项研究中，我们鉴定出 MDC1，一种参与细胞对 DNA 双链断裂反应的关键检查点蛋白，作为与 TopBP1 相关的蛋白。TopBP1 与 MDC1 的特定相互作用是由 TopBP1 的第五个 BRCT 结构域和 MDC1 的 Ser-Asp-Thr (SDT) 重复序列介导的。此外，我们证明了 TopBP1 在停滞的复制叉处的积累是由 H2AX/MDC1 信号级联促进的。此外，MDC1 对于 ATR 依赖性 Chk1 激活以响应复制应激是重要的。总之，我们的数据表明，MDC1 促进了细胞 DNA 损伤反应和 DNA 复制检查点中的几个重要步骤。
