Abstract
Mutant p53 proteins were shown to exert complex DNA-interactions in vitro, like binding to MAR-DNA, but so far it is unknown whether such interactions also occur in vivo. Therefore we analysed the binding of mutant (mut) p53 (Gly245→Ser) in Onda 11 glioma cells to cellular DNA in vivo, using p53-specific chromatin immunoprecipitation (CHIP) after in vivo cross-linking of mut p53 to genomic DNA with cisplatin. We identified genomic DNA fragments to which mut p53 (Gly245→Ser) could be cross-linked in vivo. Purified recombinant mut p53 (Gly245→Ser) was able to bind specifically to such elements in PCR-EMSA in vitro, supporting the idea that this mut p53 protein interacts with genomic DNA in vivo. The genomic DNA fragments identified are vastly different in sequence, but display as a common feature a high likelihood to adopt a non B-DNA conformation. Therefore we propose that structural determinants within these DNA elements are important for their interaction with mut p53 (Gly245→Ser) in vivo.
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Acknowledgements
We thank Dr J Davie (University of Manitoba) for providing his protocol for cisplatin cross linking; Dr T Kumanishi (Brain Research Institute, Niigata University) and Dr K Onda (Dept. of Neurosurgery, Niigata University) for providing glioma cell line Onda 11; Dr E Kim for helpful discussion; Dr M Kulesz-Martin (Mol. Pharmacology & Cancer Therapeutics, Roswell Park Cancer Institute) for providing plasmid pFASTBAC containing the cDNA for the mut p53 (Ser245), Ms G Warnecke and Ms M Kurth for their technical assistance, and Ms M Hintz-Malchow for secretarial help. This study was supported by grant De 212/19-3 from the Deutsche Forschungsgemeinschaft, EU contract No. QLG1-1999-00273, Merck KgaA, Darmstadt, Germany, and the Fonds der Chemischen Industrie. H Koga was supported by a fellowship from the Alexander von Humboldt Foundation. The Heinrich-Pette-Institut is financially supported by the Bundesministerium für Gesundheit and the Freie und Hansestadt Hamburg.
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Koga, H., Deppert, W. Identification of genomic DNA sequences bound by mutant p53 protein (Gly245→Ser) in vivo. Oncogene 19, 4178–4183 (2000). https://doi.org/10.1038/sj.onc.1203745
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DOI: https://doi.org/10.1038/sj.onc.1203745
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