Regulation of Cisplatin Resistance and Homologous Recombinational Repair by the TFIIH Subunit XPD

ABSTRACT We have recently completed screening of the National Cancer Institutehuman tumor cell line panel and demonstrated that among four nucleo-tide excision repair proteins (XPA, XPB, XPD, and ERCC1), only theTFIIH subunit XPD endogenous protein levels correlate with alkylatingagent drug resistance. In the present study, we extended this work byinvestigating the biological consequences of XPD overexpression in thehuman glioma cell line SK-MG-4. Our results indicate that XPD overex-pression in SK-MG-4 cells leads to cisplatin resistance without affectingthe nucleotide excision repair activity or UV light sensitivity of the cell. Incontrast, in SK-MG-4 cells treated with cisplatin, XPD overexpressionleads 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 ourknowledge, this is the first description of functional cross-talk betweenXPD and Rad51, which leads to bifunctional alkylating agent drug resist-ance and accelerated removal of interstrand cross-links.