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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17 Scopus citations

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

Bibliographical note

Funding Information:
This research was supported by the Grant Agency of the Ministry of Health of the Czech Republic (NR8562-4/2005), the Grant Agency of the Czech Republic (Grants 305/05/2030 and 203/06/1239), Ministry of Education of the CR (MSMT LC06030) and the Academy of Sciences of the Czech Republic (Grants 1QS500040581 and KAN200200651). J.K. is the international research scholar of the Howard Hughes Medical Institute. The research of B.M. was supported in part by a grant to Saint Olaf College, Minnesota, from the Howard Hughes Medical Institute through the Undergraduate Science Education Program. The authors also acknowledge that their participation in the EU COST Actions D20 and D21 (Grants MSMT CR 1P05OC070, 1P05OC071, 1P05OC072) enabled them to exchange regularly the most recent ideas in the field of platinum anticancer drugs with several European colleagues.

Keywords

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

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