In vivo recombination after chronic damage exposure falls to below spontaneous levels in "recombomice".
In vivo recombination after chronic damage exposure falls to below spontaneous levels in "recombomice".
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DOI：
10.1158/1541-7786.567.2.10
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发表时间：
2004-10
期刊：
影响因子：
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通讯作者：
O. Kovalchuk;Carrie A. Hendricks;S. Cassie;Andrew J Engelward;B. Engelward
中科院分区：
文献类型：
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作者：
O. Kovalchuk;Carrie A. Hendricks;S. Cassie;Andrew J Engelward;B. Engelward
所有形式的癌症都是由基因表达的遗传变化引起的。尽管点突变已被广泛研究，但对同源重组事件知之甚少，尽管它在引起序列重排中起着促进肿瘤发生的作用。虽然允许检测点突变的转基因小鼠为体内点突变研究提供了基础工具，但直到最近，专门设计用于检测体内体细胞组织同源重组事件的转基因小鼠还不存在。因此，我们创建了荧光黄色直接重复小鼠，首次实现了体内重组细胞的自动检测。在这里，我们证明了急性剂量的电离辐射诱导荧光黄色直接重复小鼠的重组，提供了电离辐射诱导体内皮肤组织同源重组的第一个直接证据。相反，在慢性照射条件下给予的相同总剂量的辐射抑制重组的水平明显低于未照射动物的水平。此外，在长期辐照动物的组织中，整体甲基化被抑制，关键的DNA修复蛋白被诱导（特别是AP内切酶、聚合酶β和Ku70）。因此，增加对重组病变的清除可能有助于抑制同源重组。综上所述，这些研究表明，荧光黄色直接重复小鼠为研究短期和长期暴露于体内DNA损伤的重组效应提供了一种快速而有力的分析方法，并首次揭示了暴露于电离辐射会对基因组稳定性产生相反的影响，这取决于暴露的持续时间。
All forms of cancer are initiated by heritable changes in gene expression. Although point mutations have been studied extensively, much less is known about homologous recombination events, despite its role in causing sequence rearrangements that contribute to tumorigenesis. Although transgenic mice that permit detection of point mutations have provided a fundamental tool for studying point mutations in vivo, until recently, transgenic mice designed specifically to detect homologous recombination events in somatic tissues in vivo did not exist. We therefore created fluorescent yellow direct repeat mice, enabling automated detection of recombinant cells in vivo for the first time. Here, we show that an acute dose of ionizing radiation induces recombination in fluorescent yellow direct repeat mice, providing some of the first direct evidence that ionizing radiation induces homologous recombination in cutaneous tissues in vivo. In contrast, the same total dose of radiation given under chronic exposure conditions suppresses recombination to levels that are significantly below those of unexposed animals. In addition, global methylation is suppressed and key DNA repair proteins are induced in tissues from chronically irradiated animals (specifically AP endonuclease, polymerase beta, and Ku70). Thus, increased clearance of recombinogenic lesions may contribute to suppression of homologous recombination. Taken together, these studies show that fluorescent yellow direct repeat mice provide a rapid and powerful assay for studying the recombinogenic effects of both short-term and long-term exposure to DNA damage in vivo and reveal for the first time that exposure to ionizing radiation can have opposite effects on genomic stability depending on the duration of exposure.