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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >DNMTs are required for delayed genome instability caused by radiation
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DNMTs are required for delayed genome instability caused by radiation

机译：DNMT是放射线引起的基因组不稳定性延迟所必需的

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The ability of ionizing radiation to initiate genomic instability has been harnessed in the clinic where the localized delivery of controlled doses of radiation is used to induce cell death in tumor cells. Though very effective as a therapy, tumor relapse can occur in vivo and its appearance has been attributed to the radio-resistance of cells with stem celllike features. The molecular mechanisms underlying these phenomena are unclear but there is evidence suggesting an inverse correlation between radiation-induced genomic instability and global hypomethylation. To further investigate the relationship between DNA hypomethylation, radiosensitivity and genomic stability in stem-like cells we have studied mouse embryonic stem cells containing differing levels of DNA methylation due to the presence or absence of DNA methyltransferases. Unexpectedly, we found that global levels of methylation do not determine radiosensitivity. In particular, radiation-induced delayed genomic instability was observed at the Hprt gene locus only in wild-type cells. Furthermore, absence of Dnmt1 resulted in a 10-fold increase in de novo Hprt mutation rate, which was unaltered by radiation. Our data indicate that functional DNMTs are required for radiation-induced genomic instability, and that individual DNMTs play distinct roles in genome stability. We propose that DNMTS may contribute to the acquirement of radio-resistance in stem-like cells.
机译：在临床中已经利用了电离辐射引发基因组不稳定的能力，在该诊所中，控制剂量辐射的局部递送被用于诱导肿瘤细胞的细胞死亡。尽管作为疗法非常有效，但是肿瘤复发可以在体内发生，并且其出现归因于具有干细胞样特征的细胞的放射抗性。这些现象背后的分子机制尚不清楚，但有证据表明，辐射诱发的基因组不稳定性与总体低甲基化之间存在反相关关系。为了进一步研究干细胞样细胞中DNA甲基化不足，放射敏感性和基因组稳定性之间的关系，我们研究了由于存在或不存在DNA甲基转移酶而含有不同水平的DNA甲基化的小鼠胚胎干细胞。出乎意料的是，我们发现总体甲基化水平不能决定放射敏感性。特别是，仅在野生型细胞中在Hprt基因位点观察到辐射诱导的延迟基因组不稳定性。此外，不存在Dnmt1导致从头Hprt突变率增加了10倍，而辐射并未改变。我们的数据表明功能性DNMT是辐射诱导的基因组不稳定性所必需的，并且各个DNMT在基因组稳定性中发挥着独特的作用。我们建议DNMTS可能有助于干细胞样细胞中抗辐射的获得。

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