Aloyz Raquel, Xu Zhi-Yuan, Bello Vanessa, Bergeron Josée, Han Fei-Yu, Yan Yifei, Malapetsa Areti, Alaoui-Jamali Moulay A, Duncan Alessandra M V, Panasci Lawrence
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Quebec, Canada H3T 1E2.
Cancer Res. 2002 Oct 1;62(19):5457-62.
We have recently completed screening of the National Cancer Institute human tumor cell line panel and demonstrated that among four nucleotide excision repair proteins (XPA, XPB, XPD, and ERCC1), only the TFIIH subunit XPD endogenous protein levels correlate with alkylating agent drug resistance. In the present study, we extended this work by investigating the biological consequences of XPD overexpression in the human glioma cell line SK-MG-4. Our results indicate that XPD overexpression in SK-MG-4 cells leads to cisplatin resistance without affecting the nucleotide excision repair activity or UV light sensitivity of the cell. In contrast, in SK-MG-4 cells treated with cisplatin, XPD overexpression leads to increased Rad51-related homologous recombinational repair, increased sister chromatid exchanges, and accelerated interstrand cross-link removal. Moreover, we present biochemical evidence of an XPD-Rad51 protein interaction, which is modulated by DNA damage. To our knowledge, this is the first description of functional cross-talk between XPD and Rad51, which leads to bifunctional alkylating agent drug resistance and accelerated removal of interstrand cross-links.
我们最近完成了对美国国立癌症研究所人类肿瘤细胞系面板的筛选，并证明在四种核苷酸切除修复蛋白（XPA、XPB、XPD和ERCC1）中，只有TFIIH亚基XPD的内源性蛋白水平与烷化剂耐药性相关。在本研究中，我们通过研究XPD在人类胶质瘤细胞系SK-MG-4中过表达的生物学后果，扩展了这项工作。我们的结果表明，SK-MG-4细胞中XPD过表达导致顺铂耐药，而不影响细胞的核苷酸切除修复活性或对紫外线的敏感性。相反，在用顺铂处理的SK-MG-4细胞中，XPD过表达导致Rad51相关的同源重组修复增加、姐妹染色单体交换增加以及链间交联去除加速。此外，我们提供了XPD与Rad51蛋白相互作用的生化证据，这种相互作用受DNA损伤调节。据我们所知，这是首次描述XPD与Rad51之间的功能性相互作用，这种相互作用导致对双功能烷化剂耐药并加速链间交联的去除。
