The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase
The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase
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DOI：
10.1038/sj.onc.1207462
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发表时间：
2004-05-06
期刊：
影响因子：
8
通讯作者：
Harris, CC
中科院分区：
文献类型：
--
作者：
Yang, O;Zhang, R;Harris, CC
在复制错误修复过程中，人类MSH2/6复合体对于错配识别至关重要。虽然错配修复成分与DNA同源重组修复有关，但hMSH2/6在这一途径中的确切功能尚不清楚。在这里，我们发现重组hMSH2/6蛋白复合物刺激了Bloom's综合征基因产物BLM在体外处理Holliday连接的能力，这种活性也可能受到p53的调节。与这些观察结果一致，hMSH6在羟基脲诱导的RAD51核灶中与BLM和磷酸丝氨酸15-p53共定位，这可能对应于假定的DNA复制分叉停滞的位置，更可能导致DNA双链断裂。此外，我们发现hMSH2和hMSH6与BLM、p53和RAD51共免疫沉淀。在hMSH2-或hmsh6缺陷细胞中，RAD51病灶的数量和BLM-p53-RAD51复合物的数量均增加。这些数据表明，在双链断裂修复过程中，hMSH2/6与BLM-p53-RAD51形成了一个复合物，以响应受损的DNA分叉。
The human MSH2/6 complex is essential for mismatch recognition during the repair of replication errors. Although mismatch repair components have been implicated in DNA homologous recombination repair, the exact function of hMSH2/6 in this pathway is unclear. Here, we show that the recombinant hMSH2/6 protein complex stimulated the ability of the Bloom's syndrome gene product, BLM, to process Holliday junctions in vitro, an activity that could also be regulated by p53. Consistent with these observations, hMSH6 colocalized with BLM and phospho-ser15-p53 in hydroxyurea-induced RAD51 nuclear foci that may correspond to the sites of presumed stalled DNA replication forks and more likely the resultant DNA double-stranded breaks. In addition, we show that hMSH2 and hMSH6 coimmunoprecipitated with BLM, p53, and RAD51. Bot h the number of RAD51 foci and the amount of the BLM-p53-RAD51 complex are increased in hMSH2- or hMSH6-deficient cells. These data suggest that hMSH2/6 formed a complex with BLM-p53-RAD51 in response to the damaged DNA forks during double-stranded break repair.