1,2-GG intrastrand cross-link of antitumor dinuclear bifunctional platinum compound with spermidine linker inhibits DNA polymerization more effectively than the cross-link of conventional cisplatin

Branden Moriarity, Olga Nováková, Nicholas Farrell, Viktor Brabec, Jana Kašpárková

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Abstract

In order to learn more about the molecular basis for the inhibition of DNA replication produced by antitumor platinum drugs, we investigated DNA polymerization using DNA templates site-specifically modified with the 1,2-GG intrastrand cross-link of dinuclear bifunctional [{trans -PtCl (NH3)2}2 {l-spermidine-N 1,N 8}]3 + (BBR3571) or conventional mononuclear cisplatin. These cross-links which have the same nature, but differ in the size and character of the conformational alteration induced in double-helical DNA, were analyzed for bypass ability with reverse transcriptase of human immunodeficiency virus type 1 and Klenow fragment of DNA polymerase I deficient in exonuclease activity. We found that the 1,2-GG intrastrand CL of BBR3571 inhibited DNA translesion synthesis markedly more than the same adduct of cisplatin. This result was explained by a larger size of the cross-link of BBR3571 and by a flexibility induced in DNA by this cross-link which can make the productive binding of this adduct at the polymerase site more difficult.

Original languageEnglish (US)
Pages (from-to)264-272
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume459
Issue number2
DOIs
StatePublished - Mar 15 2007

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Keywords

  • Antitumor platinum drugs
  • Chemical probes of DNA conformation
  • Cisplatin
  • DNA conformation
  • DNA replication
  • Gel electrophoresis
  • Translesion DNA synthesis

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