Polymerase η deficiency in the xeroderma pigmentosum variant uncovers an overlap between the S phase checkpoint and double-strand break repair
Polymerase η deficiency in the xeroderma pigmentosum variant uncovers an overlap between the S phase checkpoint and double-strand break repair
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DOI：
10.1073/pnas.130182897
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发表时间：
2000-07-05
影响因子：
11.1
通讯作者：
Cleaver, JE
中科院分区：
文献类型：
--
作者：
Limoli, CL;Giedzinski, E;Cleaver, JE
着色性干皮病变异体（XPV）是一种涉及高水平的太阳能诱导的癌症的遗传性疾病，其具有正常的切除修复，但由于损伤特异性聚合酶hRAD 30的突变，在紫外线照射后显示出有缺陷的DNA复制。我们以前发现，诱导姐妹染色单体交换的紫外线照射大大增强转化XPV细胞，表明重组途径的激活。我们现在已经确定XPV细胞利用涉及hMre 11/hRad 50/Nbs 1蛋白复合物的同源重组途径，而不是Rad 51重组途径。hMre 11复合物形成于停滞的复制叉，与增殖细胞核抗原相关。相反，在X射线损伤的细胞中，hMre 11和增殖细胞核抗原之间没有关联。这种重组途径在缺乏功能性p53途径的转化的XPV细胞中具有更大的重要性，并且可以在切除缺陷的XPA成纤维细胞和正常细胞中以较低的频率检测到，UV损伤后DNA复制停滞，因此相关的S期检查点是一个复杂的过程，可以募集在修复X射线引起的双链断裂中具有主要作用的重组途径，因此，XPV患者中日光致癌作用升高的症状可能与皮肤细胞中双链断裂和重新连接导致的基因组重排增加有关，其中p53被UV诱导的突变灭活。
The xeroderma pigmentosum variant (XPV) is a genetic disease involving high levels of solar-induced cancer that has normal excision repair but shows defective DNA replication after UV irradiation because of mutations in the damage-specific polymerase hRAD30. We previously found that the induction of sister chromatid exchanges by UV irradiation was greatly enhanced in transformed XPV cells, indicating the activation of a recombination pathway. We now have identified that XPV cells make use of a homologous recombination pathway involving the hMre11/hRad50/Nbs1 protein complex, but not the Rad51 recombination pathway. The hMre11 complexes form at arrested replication forks, in association with proliferating cell nuclear antigen. In x-ray-damaged cells, in contrast, there is no association between hMre11 and proliferating cell nuclear antigen. This recombination pathway assumes greater importance in transformed XPV cells that lack a functional p53 pathway and can be detected at lower frequencies in excision-defective XPA fibroblasts and normal cells, DNA replication arrest after UV damage, and the associated S phase checkpoint is therefore a complex process that can recruit a recombination pathway that has a primary role in repair of double-strand breaks from x-rays, The symptoms of elevated solar carcinogenesis in XPV patients therefore may be associated with increased genomic rearrangements that result from double-strand breakage and rejoining in cells of the skin in which p53 is inactivated by UV-induced mutations.