Mechanisms of chromosomal translocations and nuclear dynamics
Mechanisms of chromosomal translocations and nuclear dynamics
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染色体易位和核动力学机制
DOI：
10.11412/jspho.58.346
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
孫 継英
中科院分区：
文献类型：
--
作者：
田代 聡;孫 継英
染色体易位是由 DNA 损伤剂引起的最常见的基因重排类型之一。涉及 11q23 的染色体易位是继发性白血病中最常见的染色体畸变。然而，染色体易位的分子机制仍然很大程度上未知。我们发现，ATM 激酶（一种 DNA 损伤信号调节因子）的缺陷会增加依托泊苷处理的细胞中 11q23 染色体易位的发生率。我们还观察到，依托泊苷处理后，INO80 染色质重塑复合物的一个亚基 ARP8 的磷酸化受到 ATM 的调节，并减弱了 ARP8 与 INO80 的相互作用。 ATM 调节的 ARP8 磷酸化可减少 INO80 和 RAD51（一种参与 DNA 修复的重组酶）在断点簇区域的过度负载。这些发现表明，ATM 调节的 ARP8 磷酸化在维持 DNA 修复的准确性以防止依托泊苷诱导的 11q23 异常方面发挥着重要作用。我们还检查了 11q23 易位断点周围高阶核结构的变化。对染色体易位机制的研究将有助于预防儿童期癌症治疗的晚期影响。
Chromosomal translocations are one of the most common types of genetic rearrangement induced by agents that damage DNA. Chromosomal translocations involving 11q23 are the most frequent chromosomal aberrations in secondary leukemia. The molecular mechanisms of chromosomal translocations, however, remain largely unknown. We found that a defect of ATM kinase, a DNA damage signaling regulator, increases the incidence of 11q23 chromosomal translocation in etoposide-treated cells. We also observed that the phosphorylation of ARP8, a subunit of the INO80 chromatin remodeling complex, after etoposide treatment is regulated by ATM and attenuates ARP8 interaction with INO80. The ATM-regulated phosphorylation of ARP8 reduces the excessive loading of your INO80 and RAD51, a recombinase involved in DNA repair, onto the breakpoint cluster region. These findings suggest that the phosphorylation of ARP8 regulated by ATM plays an important role in maintaining the accuracy of DNA repair to prevent etoposide-induced 11q23 abnormalities. We also examined the changes of higher-order nuclear structures around breakpoints of 11q23 translocations. Studies of mechanisms of chromosomal translocations will contribute to the prevention of late effects of cancer treatment in childhood.