Homologous and non-homologous recombination differentially affect DNA damage repair in mice
Homologous and non-homologous recombination differentially affect DNA damage repair in mice
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DOI：
10.1093/emboj/19.7.1703
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发表时间：
2000-04-03
期刊：
影响因子：
11.4
通讯作者：
Kanaar, R
中科院分区：
文献类型：
--
作者：
Essers, J;van Steeg, H;Kanaar, R
电离辐射和链间 DNA 交联化合物由于对增殖细胞具有极大的遗传毒性，因此提供了重要的癌症治疗方法。这些治疗的功效和这些药物的诱变潜力均受到细胞修复所造成的 DNA 损伤的能力的调节。在这里，我们证明同源重组缺陷的 mRAD54(-/-) 小鼠在胚胎阶段对电离辐射过敏，但出乎意料的是，在成年阶段则不然。然而，在成年阶段，mRAD54 缺陷会显着加剧严重联合免疫缺陷 (scid) 小鼠的电离辐射敏感性，这些小鼠通过 DNA 末端连接进行的 DNA 双链断裂修复受损。相比之下，无论发育阶段如何，mRAD54-/-小鼠对链间DNA交联化合物丝裂霉素C高度敏感。这些结果表明，哺乳动物中两种主要的DNA双链断裂修复途径具有重叠和专门的作用，并且这些途径对修复电离辐射诱导的DNA损伤的相对贡献在动物发育过程中发生变化。
Ionizing radiation and interstrand DNA crosslinking compounds provide important treatments against cancer due to their extreme genotoxicity for proliferating cells. Both the efficacies of such treatments and the mutagenic potential of these agents are modulated by the ability of cells to repair the inflicted DNA damage. Here we demonstrate that homologous recombination-deficient mRAD54(-/-) mice are hypersensitive to ionizing radiation at the embryonic but, unexpectedly, not at the adult stage. However, at the adult stage mRAD54 deficiency dramatically aggravates the ionizing radiation sensitivity of severe combined immune deficiency (scid) mice that are impaired in DNA double-strand break repair through DNA end-joining. In contrast, regardless of developmental stage, mRAD54-/- mice are hypersensitive to the interstrand DNA crosslinking compound mitomycin C, These results demonstrate that the two major DNA double-strand break repair pathways in mammals have overlapping as well as specialized roles, and that the relative contribution of these pathways towards repair of ionizing radiation-induced DNA damage changes during development of the animal.