Department of Cellular Biology, RIRBM, Hiroshima University, Hiroshima, Japan.
PLoS One. 2010 Oct 27;5(10):e13554. doi: 10.1371/journal.pone.0013554.
Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Chromosome translocations involving the MLL gene on 11q23 are the most frequent chromosome abnormalities in secondary leukemias associated with chemotherapy employing etoposide, a topoisomerase II poison. Here we show that ATM deficiency results in the excessive binding of the DNA recombination protein RAD51 at the translocation breakpoint hotspot of 11q23 chromosome translocation after etoposide exposure. Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots.
由 DNA 损伤剂（如电离辐射和某些化疗药物）诱导的染色体易位会改变遗传信息，导致恶性转化。共济失调毛细血管扩张突变（ATM）蛋白是一种 DNA 损伤信号调节因子，其缺失或失活会增加染色体易位的发生率。然而，ATM 如何保护细胞免受染色体易位仍然不清楚。涉及 11q23 上 MLL 基因的染色体易位是与拓扑异构酶 II 抑制剂依托泊苷化疗相关的继发性白血病中最常见的染色体异常。在这里，我们发现 ATM 缺陷导致在依托泊苷暴露后，11q23 染色体易位的易位断点热点处的 DNA 重组蛋白 RAD51 过度结合。复制蛋白 A（RPA）和染色质重塑因子 INO80 的结合也增加了，它们有助于 RAD51 加载到受损 DNA 上，而 ATM 缺陷则增加了这种结合。因此，除了激活 DNA 损伤信号外，ATM 还可以通过防止重组修复蛋白过度加载到易位断点热点上来避免染色体易位。
