Different recognition of DNA modified by aatitumor cisplatin and its clinically ineffective trans isomer by tumor suppressor protein p53
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
11279186
DOI
10.1074/jbc.m101224200
PII: S0021-9258(19)32027-7
Knihovny.cz E-resources
- MeSH
- DNA Adducts metabolism MeSH
- Cell Line MeSH
- Cisplatin metabolism MeSH
- Isomerism MeSH
- Consensus Sequence MeSH
- Humans MeSH
- Tumor Suppressor Protein p53 metabolism MeSH
- Oligodeoxyribonucleotides chemistry metabolism MeSH
- Recombinant Proteins metabolism MeSH
- Base Sequence MeSH
- Spodoptera MeSH
- Substrate Specificity MeSH
- Transfection MeSH
- Binding Sites MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- cisplatin-DNA adduct MeSH Browser
- Cisplatin MeSH
- Tumor Suppressor Protein p53 MeSH
- Oligodeoxyribonucleotides MeSH
- Recombinant Proteins MeSH
- transplatin MeSH Browser
The p53 gene encodes a nuclear phosphoprotein that is biologically activated in response to genotoxic stresses including treatment with anticancer platinum drugs. The DNA binding activity of p53 protein is crucial for its tumor suppressor function. DNA interactions of active wild-type human p53 protein with DNA fragments and oligodeoxyribonucleotide duplexes modified by antitumor cisplatin and its clinically ineffective trans isomer (transplatin) were investigated by using a gel mobility shift assay. It was found that DNA adducts of cisplatin reduced binding affinity of the consensus DNA sequence to p53, whereas transplatin adducts did not. This result was interpreted to mean that the precise steric fit required for the formation and stability of the tetrameric complex of p53 with the consensus sequence cannot be attained, as a consequence of severe conformational perturbations induced in DNA by cisplatin adducts. The results also demonstrate an increase of the binding affinity of p53 to DNA lacking the consensus sequence and modified by cisplatin but not by transplatin. In addition, only major 1,2-GG intrastrand cross-links of cisplatin are responsible for this enhanced binding affinity of p53. The data base on structures of various DNA adducts of cisplatin and transplatin reveals distinctive structural features of 1,2-intrastrand cross-links of cisplatin, suggesting a unique role for this adduct in the binding of p53 to DNA lacking the consensus sequence. The results support the hypothesis that the mechanism of antitumor activity of cisplatin may also be associated with its efficiency to affect the binding affinity of platinated DNA to active p53 protein.
References provided by Crossref.org
Recognition of Local DNA Structures by p53 Protein
