Recognition of DNA modified by trans-[PtCl2NH3(4-hydroxymethylpyridine)] by tumor suppressor protein p53 and character of DNA adducts of this cytotoxic complex

doi:10.1111/j.1742-4658.2005.05061.x

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Wiley InterScience

FEBS Journal

Volume 273 Issue 2, Pages 301 - 314

Published Online: 20 Dec 2005

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Published on behalf of the Federation of European Biochemical Societies

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Recognition of DNA modified by trans-[PtCl₂NH₃(4-hydroxymethylpyridine)] by tumor suppressor protein p53 and character of DNA adducts of this cytotoxic complex

Kristýna Stehlíková ¹*, Jana Kašpárková ¹*, Olga Nováková ¹*, Alberto Martínez ² , Virtudes Moreno ² and Viktor Brabec ¹

1 Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
2 Departament de Química Inorgánica, Universitat de Barcelona, Barcelona, Spain

Correspondence to V. Brabec, Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic
Fax: +420 541240499
Tel: +420 541517148 E-mail: brabec@ibp.cz
URL: http://www.ibp.cz/labs/BNAIAD

*The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint first authors.

KEYWORDS

antitumor • conformation • DNA • p53 • platinum drug

ABSTRACT

trans-[PtCl₂NH₃(4-Hydroxymethylpyridine)] (trans-PtHMP) is an analogue of clinically ineffective transplatin, which is cytotoxic in the human leukemia cancer cell line. As DNA is a major pharmacological target of antitumor platinum compounds, modifications of DNA by trans-PtHMP and recognition of these modifications by active tumor suppressor protein p53 were studied in cell-free media using the methods of molecular biology and biophysics. Our results demonstrate that the replacement of the NH₃ group in transplatin by the 4-hydroxymethylpyridine ligand affects the character of DNA adducts of parent transplatin. The binding of trans-PtHMP is slower, although equally sequence-specific. This platinum complex also forms on double-stranded DNA stable intrastrand and interstrand cross-links, which distort DNA conformation in a unique way. The most pronounced conformational alterations are associated with a local DNA unwinding, which was considerably higher than those produced by other bifunctional platinum compounds. DNA adducts of trans-PtHMP also reduce the affinity of the p53 protein to its consensus DNA sequence. Thus, downstream effects modulated by recognition and binding of p53 protein to DNA distorted by trans-PtHMP and transplatin are not likely to be the same. It has been suggested that these different effects may contribute to different antitumor effects of these two transplatinum compounds.