Evidence for a role of vertebrate Rad52 in the repair of topoisomerase II-mediated DNA damage
Evidence for a role of vertebrate Rad52 in the repair of topoisomerase II-mediated DNA damage
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DOI：
10.1089/dna.2005.24.388
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发表时间：
2005-06-01
影响因子：
3.1
通讯作者：
Koyama, H
中科院分区：
文献类型：
--
作者：
Adachi, N;Iiizumi, S;Koyama, H
DNA拓扑异构酶II （Top2）抑制剂是有用的抗癌药物，主要是由于它们能够诱导DNA双链断裂（DSBs）。在酵母中，这些dsb几乎完全通过依赖于rad52的同源重组（HR）修复。然而，我们最近的研究表明，在脊椎动物细胞中，这种损伤主要通过非同源末端连接修复，而不是通过HR修复。这一发现，连同先前的观察结果，即RAD52的破坏不会严重影响脊椎动物细胞的HR，使得RAD52极不可能有助于修复top2介导的DNA损伤。然而，在本文中，我们发现缺乏Rad52的鸡细胞对Top2抑制剂VP-16的敏感性增加。值得注意的是，RAD52-null细胞的过敏水平与RAD54-null细胞相当，尽管只是在高剂量下。因此，我们的数据首次证明了脊椎动物细胞中与Rad52缺失相关的主要修复缺陷。
DNA topoisomerase II (Top2) inhibitors are useful as anticancer agents, mostly by virtue of their ability to induce DNA double-strand breaks (DSBs). These DSBs are repaired almost exclusively by Rad52-dependent homologous recombination (HR) in yeast. However, we have recently shown that in vertebrate cells such lesions are primarily repaired by nonhomologous end-joining, but not HR. This finding, taken together with previous observations that disruption of RAD52 does not severely affect HR in vertebrate cells, makes it highly unlikely that Rad52 contributes to the repair of Top2-mediated DNA damage. However, in this paper we show that chicken cells lacking Rad52 do exhibit increased sensitivity to the Top2 inhibitor VP-16. Remarkably, the level of hypersensitivity of RAD52-null cells was comparable to that of RAD54-null cells, albeit only at high doses. Our data thus provide the first demonstration of a major repair defect associated with loss of Rad52 in vertebrate cells.