Drosophila ATR in double-strand break repair
Drosophila ATR in double-strand break repair
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DOI：
10.1534/genetics.106.067330
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发表时间：
2007-03-01
期刊：
影响因子：
3.3
通讯作者：
Sekelsky, Jeff
中科院分区：
文献类型：
--
作者：
LaRocque, Jeannine R.;Jaklevic, Burnley;Sekelsky, Jeff
细胞感知和响应DNA损伤的能力对基因组稳定性至关重要。反应的一个重要方面是细胞周期的停滞，大概是为了有时间进行修复。共济失调毛细血管扩张突变（ATM）和ATR是必不可少的细胞周期控制，但一些观察表明，他们也发挥了直接作用的DNA修复。果蝇ATR的直系同源物MEI-41介导DNA损伤依赖性G2-M检查点。我们研究了MEI-41在修复由P元件切除诱导的双链断裂（DSB）中的作用。我们发现mei-41突变体在完成同源重组修复的后期步骤中存在缺陷，但在末端连接修复中没有缺陷。我们假设这些修复缺陷是检查点控制丧失的结果。为了测试这一点，我们从遗传上降低了有丝分裂细胞周期蛋白水平，并检查了grp（DmChk 1）和lok（DmChk 2）突变体的修复。我们的研究结果表明，修复缺陷的一个重要组成部分是由于MEI-41依赖的细胞周期调控的损失。然而，这并不能解释我们观察到的所有缺陷。我们提出MEI-41在DSB修复中的新作用，独立于Chk 1/Chk 2介导的检查点反应。
The ability of a cell to sense and respond to DNA damage is essential for genome stability. An important aspect of the response is arrest of the cell cycle, presumably to allow time for repair. Ataxia telangiectasia mutated (ATM) and ATR are essential for such cell-cycle control, but some observations suggest that they also play a direct role in DNA repair. The Drosophila ortholog of ATR, MEI-41, mediates the DNA damage-dependent G2-M checkpoint. We examined the role of MEI-41 in repair of double-strand breaks (DSBs) induced by P-element excision. We found that mei-41 mutants are defective in completing the later steps of homologous recombination repair, but have no defects in end-joining repair. We hypothesized that these repair defects are the result of loss of checkpoint control. To test this, we genetically reduced mitotic cyclin levels and also examined repair in grp (DmChk1) and lok (DmChk2) mutants. Our results suggest that a significant component of the repair defects is due to loss of MEI-41-dependent cell cycle regulation. However, this does not account for all of the defects we observed. We propose a novel role for MEI-41 in DSB repair, independent of the Chk1/Chk2-mediated checkpoint response.