Deficient gene specific repair of cisplatin-induced lesions in Xeroderma pigmentosum and Fanconi's anemia cell lines

Cisplatin is a chemotherapeutic agent known to cause DNA damage.The cytotoxicity of this drug is believed to result from theformation of DNA intrastrand adducts (IA) and DNA interstrandcrosslinks (ICL). While there are many studies on DNA repairof cisplatin damage at the overall level of the genome in varioushuman cell lines, there is little information on the gene-specificrepair. In this report, we have measured the formation and repairof cisplatin induced DNA adducts in the dihydrofolate reductase(DHFR) and ribosomal RNA (rRNA) genes in three cell lines: normalhuman fibroblasts, Fanconi's anemia complementation group A(FAA) and Xeroderma pigmentosum complementation group A (XPA).It is generally thought that XPA cells lack nucleotide excisionrepair and that FAA cells are deficient in the repair of DNAICL. We find that normal human fibroblast cells repair 84% ofthe ICL in the DHFR gene after 24 h, whereas XPA and FAA celllines only repaired 32 and 50% of the ICL respectively. Furthermore,69% of the cisplatin IA in the DHFR gene were repaired in 24h in normal human fibroblasts compared to 22% for XPA and 24%for FAA cells. The repair of the rRNA gene was less efficientthan in the DHFR gene, but the relative pattern between thedifferent cell lines was similar to that of the DHFR gene. Wethus find that FAA cells are deficient not only in the genespecific repair of cisplatin ICL, but also in the gene specificrepair of the more common cisplatin IA. XPA cells are normallythought to be without any nucleotide excision repair capacity,but our data could support a slight ICL unhooking activity.