Sequence specificity of mutation induced by the anti-tumor drug cisplatin in the CHO <i>aprt</i> gene

Abstract

Cis-diammine dichloroplatinum (cisplatin) is an effective anti-cancer drug which forms adducts with DNA, in both bacterial and mammalian cells. It is suspected of producing tumors as well. To determine the molecular nature of genetic alterations induced by cisplatin, we cloned and sequenced cisplatin-induced mutants in the adenine phosphoribosyltransferase (aprt) gene of Chinese hamster ovary (CHO) cells. Mutation by cisplatin appears to be targeted as the sites of mutation are consistent with the known binding specificity of cisplatin. Many mutations occur at or proximal to the sequence 5'-AGG-3' and 5'-GAG-3' and include transversions, transitions, frameshifts and short deletions and duplications. Several double changes were also observed. No major rearrangements were recovered in our collection. At several locations, a number of mutants were found to be clustered within a small target region, but unlike traditional hotspots, these represent diverse changes occurring in a localized region of a few base pairs.