DNA modification with cisplatin affects sequence-specific DNA binding of p53 and p73 proteins in a target site-dependent manner.
Proteins p53 and p73 act as transcription factors in cell cycle control, regulation of cell development and/or in apoptotic pathways. Both proteins bind to response elements (p53 DNA-binding sites), typically consisting of two copies of a motif RRRCWWGYYY. It has been demonstrated previously that DNA modification with the antitumor drug cisplatin inhibits p53 binding to a synthetic p53 DNA-binding site. Here we demonstrate that the effects of global DNA modification with cisplatin on binding of the p53 or p73 proteins to various p53 DNA-binding sites differed significantly, depending on the nucleotide sequence of the given target site. The relative sensitivities of protein-DNA binding to cisplatin DNA treatment correlated with the occurrence of sequence motifs forming stable bifunctional adducts with the drug (namely, GG and AG doublets) within the target sites. Binding of both proteins to mutated p53 DNA-binding sites from which these motifs had been eliminated was only negligibly affected by cisplatin treatment, suggesting that formation of the cisplatin adducts within the target sites was primarily responsible for inhibition of the p53 or p73 sequence-specific DNA binding. Distinct effects of cisplatin DNA modification on the recognition of different response elements by the p53 family proteins may have impacts on regulation pathways in cisplatin-treated cells.
Pivonková
Hana
H
Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
Pecinka
Petr
P
Cesková
Pavla
P
Fojta
Miroslav
M
D000970:Antineoplastic Agents / Q000737:chemistry; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002945:Cisplatin / Q000737:chemistry*; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; D002945:Cisplatin