Nucleotide excision repair of melphalan monoadducts.
The nucleotide-excision repair (NER) system removes bulky DNA adducts and is thought to be involved in resistance to chemotherapeutic drugs, which act by damaging DNA. In this study, we have investigated the ability of the NER system to recognize and excise melphalan monoadducts from a 140-mer DNA substrate. We show that rodent and human cell-free extracts (CFEs) excise 26-29-nt-long oligomers from a synthetic 140-mer containing centrally located melphalan adducts. CFEs from cell lines with mutations in xeroderma pigmentosum group F or G genes did not excise these alkylated oligomers; however, mixing the two CFEs restored excision activity to the level found with wild-type CFEs. These results demonstrate the ability of the NER system to excise melphalan monoadducts, and are consistent with the hypothesis that NER may be involved in resistance to melphalan chemotherapy.
Grant
D F
DF
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA. grantdavidf@exchange.uams.edu
Bessho
T
T
Reardon
J T
JT
D000478:Alkylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism*; D016466:CHO Cells; D002474:Cell-Free System; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D004351:Drug Resistance; D006367:HeLa Cells; D006801:Humans
D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D004247:DNA