Inhibition of DNA double-strand break repair by the Ku heterodimer in mrx mutants of Saccharomyces cerevisiae.
Inhibition of DNA double-strand break repair by the Ku heterodimer in mrx mutants of Saccharomyces cerevisiae.
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DOI：
10.1016/j.dnarep.2008.09.010
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发表时间：
2009-02-01
期刊：
影响因子：
3.8
通讯作者：
Lewis LK
中科院分区：
文献类型：
--
作者：
Wasko BM;Holland CL;Resnick MA;Lewis LK
酵母rad 50和mre 11核酸酶突变体对诱导DNA双链断裂（DSB）的物理和化学试剂超敏感。这种敏感性受到抑制，升高细胞内水平的TLC 1，端粒酶的RNA亚基。抑制需要与同源重组相关的蛋白质，包括Rad 51，Rad 52，Rad 59和Exo 1，但不需要非同源末端连接（NHEJ）修复途径的基因。缺失突变实验表明，TLC 1 RNA的5′端是必需的，含有Yku 70/Yku 80复合物结合位点的片段足以抑制。不能与Yku 80蛋白结合的突变型TLC 1 RNA不增加抗性。这些和其他遗传学研究表明，Ku异源二聚体与断裂的DNA末端的关联抑制了mrna突变体中的重组，但在修复能力强的细胞或其他DNA修复单突变体中不抑制重组。支持这一模型的是，当YKU 70共失活时，mesenchymal细胞的DNA损伤抗性增强。因此，在MLB细胞中DSB的缺陷性重组修复至少由两个独立的过程引起：MLB核酸酶相关DNA末端加工的丧失和Ku对Exo 1介导的二级重组途径的抑制。
Yeast rad50 and mre11 nuclease mutants are hypersensitive to physical and chemical agents that induce DNA double-strand breaks (DSBs). This sensitivity was suppressed by elevating intracellular levels of TLC1, the RNA subunit of telomerase. Suppression required proteins linked to homologous recombination, including Rad51, Rad52, Rad59 and Exo1, but not genes of the nonhomologous end-joining (NHEJ) repair pathway. Deletion mutagenesis experiments demonstrated that the 5′ end of TLC1 RNA was essential and a segment containing a binding site for the Yku70/Yku80 complex was sufficient for suppression. A mutant TLC1 RNA unable to associate with Yku80 protein did not increase resistance. These and other genetic studies indicated that association of the Ku heterodimer with broken DNA ends inhibits recombination in mrx mutants, but not in repair-proficient cells or in other DNA repair single mutants. In support of this model, DNA damage resistance of mrx cells was enhanced when YKU70 was co-inactivated. Defective recombinational repair of DSBs in mrx cells thus arises from at least two separate processes: loss of Mrx nuclease-associated DNA end-processing and inhibition of the Exo1-mediated secondary recombination pathway by Ku.
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