Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
Nature. 2011 Feb 3;470(7332):124-8. doi: 10.1038/nature09658.
p53-binding protein 1 (53BP1) is known to be an important mediator of the DNA damage response, with dimethylation of histone H4 lysine 20 (H4K20me2) critical to the recruitment of 53BP1 to double-strand breaks (DSBs). However, it is not clear how 53BP1 is specifically targeted to the sites of DNA damage, as the overall level of H4K20me2 does not seem to increase following DNA damage. It has been proposed that DNA breaks may cause exposure of methylated H4K20 previously buried within the chromosome; however, experimental evidence for such a model is lacking. Here we found that H4K20 methylation actually increases locally upon the induction of DSBs and that methylation of H4K20 at DSBs is mediated by the histone methyltransferase MMSET (also known as NSD2 or WHSC1) in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at DSBs and the subsequent accumulation of 53BP1. Furthermore, we found that the recruitment of MMSET to DSBs requires the γH2AX-MDC1 pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated Ser 102 of MMSET. Thus, we propose that a pathway involving γH2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around DSBs, which, in turn, facilitates 53BP1 recruitment.
p53 结合蛋白 1（53BP1）是 DNA 损伤反应的重要介质，组蛋白 H4 赖氨酸 20（H4K20me2）的二甲基化对于 53BP1 募集到双链断裂（DSB）至关重要。然而，53BP1 如何特异性地靶向 DNA 损伤部位尚不清楚，因为 DNA 损伤后 H4K20me2 的总体水平似乎没有增加。有人提出，DNA 断裂可能导致先前埋藏在染色体中的甲基化 H4K20 暴露；然而，这种模型的实验证据是缺乏的。在这里，我们发现 H4K20 的甲基化实际上在 DSB 的诱导下局部增加，并且在哺乳动物中，DSB 处的 H4K20 甲基化是由组蛋白甲基转移酶 MMSET（也称为 NSD2 或 WHSC1）介导的。MMSET 的下调显著降低了 DSB 处的 H4K20 甲基化和随后的 53BP1 积累。此外，我们发现 MMSET 向 DSB 的募集需要 γH2AX-MDC1 途径；具体来说，MDC1 BRCT 结构域与磷酸化的 MMSET Ser102 之间的相互作用。因此，我们提出了一种涉及 γH2AX-MDC1-MMSET 的途径来调节 DSB 周围组蛋白上 H4K20 甲基化的诱导，这反过来又促进了 53BP1 的募集。
