Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo
Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo
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DOI：
10.1038/sj.onc.1209467
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发表时间：
2006-07-20
期刊：
影响因子：
8
通讯作者：
Kovalchuk, O.
中科院分区：
文献类型：
--
作者：
Koturbash, I.;Rugo, R. E.;Kovalchuk, O.
受辐射的细胞会在体外诱导未受辐射的旁观者细胞的染色体不稳定。尽管旁观者效应被认为与辐射诱发的继发性癌症有关，但几乎没有研究评估体内旁观者效应。此外，有人提出表观遗传变化介导旁观者效应，但很少有研究评估体内旁观者组织的表观遗传因素。在这里，我们描述了一些研究，其中小鼠单侧暴露于 X 射线照射，并评估受照射和旁观者皮肤组织的 DNA 损伤、DNA 甲基化和蛋白质表达水平。数据显示，动物身体一侧的 X 射线照射会导致 DNA 链断裂，并导致未照射的旁观者组织中 Rad51 水平增加。就表观遗传变化而言，单侧辐射会抑制直接照射组织中的整体甲基化，但在研究的给定时间点不会抑制旁观者组织中的甲基化。然而有趣的是，我们观察到旁观者组织中从头 DNA 甲基转移酶 DNMT3a 和 3b 的水平显着降低，而维持 DNA 甲基转移酶 DNMT1 的水平同时增加。此外，旁观者组织中已知参与转录沉默的两种甲基结合蛋白 MeCP2 和 MBD2 的水平也有所增加。总之，这些结果表明，辐射会在距直接受辐射组织一厘米以上的旁观者组织中引起 DNA 损伤，并表明表观遗传转录调控可能与辐射引起的旁观者效应的病因有关。
Irradiated cells induce chromosomal instability in unirradiated bystander cells in vitro. Although bystander effects are thought to be linked to radiation-induced secondary cancers, almost no studies have evaluated bystander effects in vivo. Furthermore, it has been proposed that epigenetic changes mediate bystander effects, but few studies have evaluated epigenetic factors in bystander tissues in vivo. Here, we describe studies in which mice were unilaterally exposed to X-irradiation and the levels of DNA damage, DNA methylation and protein expression were evaluated in irradiated and bystander cutaneous tissue. The data show that X-ray exposure to one side of the animal body induces DNA strand breaks and causes an increase in the levels of Rad51 in unexposed bystander tissue. In terms of epigenetic changes, unilateral radiation suppresses global methylation in directly irradiated tissue, but not in bystander tissue at given time-points studied. Intriguingly, however, we observed a significant reduction in the levels of the de novo DNA methyltransferases DNMT3a and 3b and a concurrent increase in the levels of the maintenance DNA methyltransferase DNMT1 in bystander tissues. Further more, the levels of two methyl-binding proteins known to be involved in transcriptional silencing, MeCP2 and MBD2, were also increased in bystander tissue. Together, these results show that irradiation induces DNA damage in bystander tissue more than a centimeter away from directly irradiated tissues, and suggests that epigenetic transcriptional regulation may be involved in the etiology of radiation-induced bystander effects.