Abstract
The mutagenicity and genotoxicity of cis-[Pt(NH3)2{d(GpG)-N7(1),-N7(2)}] (G*G*), the major DNA adduct of the antitumor drug cisplatin, has been investigated in Escherichia coli. A duplex bacteriophage M13 genome was constructed to contain the G*G* adduct at a specific site in the (−) strand. The singly platinated duplex genome exhibited a survival of 22% relative to that of the unplatinated control genomes, and this value rose to 38% in cells treated with ultraviolet light to induce the SOS response. Singly platinated single-stranded genomes were also produced. Replication of the single- and double-stranded genomes in vivo yielded SOS-dependent, targeted mutations at frequencies of 1.3% and 0.16%, respectively. The mutagenic specificity of G*G* in both single- and double-stranded DNA was striking in that 80–90% of the mutations occurred at the 5′-platinated G. Approximately 80% of the mutations were G → T transversions at that site. A model of mutagenesis is presented to explain this mutational specificity with respect to current understanding of platinum-DNA adduct structure.
Original language | English (US) |
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Pages (from-to) | 982-988 |
Number of pages | 7 |
Journal | Biochemistry |
Volume | 32 |
Issue number | 3 |
DOIs | |
State | Published - 1993 |
Externally published | Yes |
ASJC Scopus subject areas
- Biochemistry