Human MMS21/NSE2 is a SUMO ligase required for DNA repair
Human MMS21/NSE2 is a SUMO ligase required for DNA repair
复制标题
DOI：
10.1128/mcb.25.16.7021-7032.2005
复制
发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Yu, HT
中科院分区：
文献类型：
--
作者：
Potts, PR;Yu, HT
DNA修复是生物体基因组稳定和健康所必需的。在酵母中，由SMC 5、SMC 6、MMS 21/NSE 2和其他非SMC蛋白组成的多亚基复合物是通过同源重组进行DNA修复所必需的。酵母MMS 21蛋白是SUMO连接酶。在这里，我们表明，人类同源的MMS 21也是一个SUMO连接酶。hMMS 21刺激hSMC 6和DNA修复蛋白TRAX的类小泛素化。通过RNA干扰（RNAi）去除hMMS 21使HeLa细胞对DNA损伤诱导的凋亡敏感。野生型hMMS 21的异位表达，而不是其连接酶失活突变体，拯救了hMMS 21-RNAi细胞的这种超敏性。ATM/ATR在hMMS 21-RNAi细胞中在DNA损伤后被过度激活。一致地，hMMS 21-RNAi细胞显示出增加的磷酸-CHK 2病灶数量。最后，我们表明，hMMS 21-RNAi细胞显示出降低的能力，以修复DNA损伤所测量的彗星试验。我们的研究结果表明，人类SMC 5/6复合物和SUMO连接酶活性的hMMS 21是必要的，通过促进人类细胞中的DNA修复，防止DNA损伤诱导的凋亡。
DNA repair is required for the genomic stability and well-being of an organism. In yeasts, a multisubunit complex consisting of SMC5, SMC6, MMS21/NSE2, and other non-SMC proteins is required for DNA repair through homologous recombination. The yeast MMS21 protein is a SUMO ligase. Here we show that the human homolog of MMS21 is also a SUMO ligase. hMMS21 stimulates sumoylation of hSMC6 and the DNA repair protein TRAX. Depletion of hMMS21 by RNA interference (RNAi) sensitizes HeLa cells toward DNA damage-induced apoptosis. Ectopic expression of wild-type hMMS21, but not its ligase-inactive mutant, rescues this hypersensitivity of hMMS21-RNAi cells. ATM/ATR are hyperactivated in hMMS21-RNAi cells upon DNA damage. Consistently, hMMS21-RNAi cells show an increased number of phospho-CHK2 foci. Finally, we show that hMMS21-RNAi cells show a decreased capacity to repair DNA lesions as measured by the comet assay. Our findings suggest that the human SMC5/6 complex and the SUMO ligase activity of hMMS21 are required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair in human cells.