Human MutL-complexes monitor homologous recombination independently of mismatch repair.
Human MutL-complexes monitor homologous recombination independently of mismatch repair.
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DOI：
10.1016/j.dnarep.2008.10.011
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发表时间：
2009-02-01
期刊：
影响因子：
3.8
通讯作者：
Wiesmueller, Lisa
中科院分区：
文献类型：
--
作者：
Siehler, Simone Yasmin;Schrauder, Michael;Gerischer, Ulrike;Cantor, Sharon;Marra, Giancarlo;Wiesmueller, Lisa
错配修复蛋白的作用已经在DNA聚合酶错误后的DNA修复中得到了很好的研究。特别是在酵母中，MSH2和MSH6也与基因重组的调控有关，而MutL的同源物似乎不那么重要。到目前为止，关于人类MutL同源物hMLH1在重组中的作用知之甚少，但最近描述的分子相互作用表明参与其中。为了确定hMLH1在这一过程中的活性，我们采用了一种基于egfp的分析方法，分析了由靶向双链DNA断裂引发的DNA修复的不同机制。我们分析了12个人类细胞系统，通过诱导蛋白表达、遗传重组或RNA干扰，这些系统在hMLH1和hPMS1和hPMS2状态上存在差异。我们证明hMLH1及其复合伙伴hPMS1和hPMS2下调保守同源重组（HR），特别是当涉及只有短段不间断同源性的DNA序列时。出乎意料的是，hMSH2对于这种效果是可有可无的。此外，损伤信号激酶ATM及其底物BLM和BACH1并不是严格必需的，但ATM/ atr信号组分的联合作用可能介导抗重组作用。我们的数据表明，在一个可能导致有害的基因组重排的过程中，hmutl复合物具有保护作用，其方式不依赖于错配修复。
The role of mismatch repair proteins has been well studied in the context of DNA repair following DNA polymerase errors. Particularly in yeast, MSH2 and MSH6 have also been implicated in the regulation of genetic recombination, whereas MutL homologs appeared to be less important. So far, little is known about the role of the human MutL homolog hMLH1 in recombination, but recently described molecular interactions suggest an involvement. To identify activities of hMLH1 in this process, we applied an EGFP-based assay for the analysis of different mechanisms of DNA repair, initiated by a targeted double-stranded DNA break. We analysed 12 human cellular systems, differing in the hMLH1 and concomitantly in the hPMS1 and hPMS2 status via inducible protein expression, genetic reconstitution, or RNA interference. We demonstrate that hMLH1 and its complex partners hPMS1 and hPMS2 downregulate conservative homologous recombination (HR), particularly when involving DNA sequences with only short stretches of uninterrupted homology. Unexpectedly, hMSH2 is dispensable for this effect. Moreover, the damage-signaling kinase ATM and its substrates BLM and BACH1 are not strictly required, but the combined effect of ATM/ATR-signaling components may mediate the anti-recombinogenic effect. Our data indicate a protective role of hMutL-complexes in a process which may lead to detrimental genome rearrangements, in a manner which does not depend on mismatch repair.
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