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Novel interactions of mutant p53 with genomic DNA in vitro and in vivo


Mutated forms of p53 (mutp53) are often expressed in a variety of human tumours. In addition to loss of function of the p53 tumour suppressor, mutant p53s contribute to malignant process by gain of novel functions that enhance transformed properties of cells and resistance to anti-cancer therapy in vitro, and increase tumorigenecity, invasiveness and metastasis ability in vivo.

Mutp53 has lost the sequence-specific DNA binding properties of wtp53, but retained its ability to specifically interact with non-B D NA elements with high affinity. Structure-selective DNA binding of mutp53 supposedly is important for the postulated "gain of function" activities of mutp53. To analyze this postulated oncogenic potential of mutp53 proteins we chose the approach of chromatin immunoprecipitation assay (ChIP) to identify genomic DNA fragments directly bound by mutp53 in vivo.

In our previous study we used glioblastoma cells from which we isolated genomic DNA bound by two different mutant Arg273Cys and Arg273His p53 proteins by preparative ChIP. About 200 DNA fragments were identified by crosslink mutp53 to DNA in vivo. Sequence analysis revealed that genomic DNA fragments contain human repetitive elements and potential MAR/SAR elements.

In addition, genes directly connected to cancer such as suppressor proteins, drug transporters, oncogenes, cellular and extra-cellular transporters and chromatin remodelling factors were found. The identified genes are expressed and functional in glioblastoma. The characterization of DNA sequences bound by mutp53 will continue by using several DNA binding assays in vitro and bioinformatic approaches. Several functional analyses of obtained genes will be investigated.

We suppose that study of the mechanism of mutp53 DNA binding together with functional study of newly genes directly connected to mutp53 by ChIP will help to understand of mutp53 oncogenic potential.

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