Importance of the cell cycle phase for the choice of the appropriate DSB repair pathway, for genome stability maintenance -: The trans-S double-strand break repair model
Importance of the cell cycle phase for the choice of the appropriate DSB repair pathway, for genome stability maintenance -: The trans-S double-strand break repair model
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DOI：
10.4161/cc.7.1.5149
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发表时间：
2008-01-01
期刊：
影响因子：
4.3
通讯作者：
Lopez, Bernard S.
中科院分区：
文献类型：
--
作者：
Delacote, Fabien;Lopez, Bernard S.
DNA双链断裂（DSB）是一种高度有害的病变，可导致基因组重排。两种主要途径竞争DSB修复：同源重组（HR）和非同源末端连接（NHEJ）。根据细胞周期阶段的不同，选择一种DSB修复途径将确保基因组的稳定性维持，相反，将增加遗传不稳定性的风险。姊妹染色单体的HR是维持基因组稳定性的有效方法，因为损伤发生在复制后阶段。然而，在G(1)检查点缺陷的细胞中，在G(1)期产生的dsb没有被NHEJ修复，可以进入S期，并在S/G(2)期后期被HR处理。我们提出“跨s DSB修复”模型来解释这些数据。在这种情况下，HR不能使用姐妹染色单体（在同一位点也被破坏），因此被迫使用分散在基因组中的异位同源序列，增加了遗传不稳定的风险。这表明两种DSB修复途径可以在细胞周期中相互竞争，并强调了细胞周期检查点和适当的DNA修复途径之间的关联对基因组稳定性维持的重要性。
A DNA double-strand break (DSB) is a highly harmful lesion that can lead to genome rearrangements. Two main pathways compete for DSB repair: homologous recombination (HR) and nonhomologous end-joining (NHEJ). Depending on the cell cycle phase, the choice of one DSB repair pathway over the other will secure genome stability maintenance or in contrast will increase the risk of genetic instability. HR with the sister chromatid is an efficient way to maintain genome stability, for damage occurring at a post-replication stage. However, in G(1) checkpoint-defective cells, DSBs produced in the G(1) phase and not repaired by NHEJ, can progress through S phase and be processed by HR in late S/G(2) phase. We propose the "trans-S DSB repair" model to account for these data. In this situation HR cannot use the sister chromatid (which is also broken at the same locus) and is thus forced to use ectopic homologous sequences dispersed through the genome, increasing the risk of genetic instability. This shows that the two DSB repair pathways can compete through the cell cycle and underlines the importance of the association between the cell cycle checkpoint and the appropriate DNA repair pathway for genome stability maintenance.