Abstract
p53 and DNA methylation play key roles in the maintenance of genome stability. In this work, we demonstrate that the two mechanisms are linked and that p53 plays a role in the maintenance of the DNA methylation levels. The loss of p53 was shown to induce loss of DNA methylation in the TROP1 gene, a human cancer-expressed locus that undergoes amplification when hypomethylated. This demethylation was reverted by the reintroduction of a wild-type TP53 (wtTP53) in the TP53-null cells. Using a gene-amplification assay in vivo, we demonstrate that the loss of p53 leads to a demethylation-dependent TROP1 gene amplification. The induction of gene amplification was reverted by the expression of a wtTP53 gene or by in vitro methylation of the transfected DNA with the Sss I DNA methylase. Taken together, these findings demonstrate that the inactivation of TP53 induces loss of DNA methylation and DNA methylation-dependent gene amplification.
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Acknowledgements
We thank Dr M Tainsky for kindly supplying the Li–Fraumeni cells and Drs A Sacchi and E Giulotto for useful discussions. We gratefully acknowledge the support of the Italian Association for Cancer Research (AIRC).
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Nasr, A., Nutini, M., Palombo, B. et al. Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene. Oncogene 22, 1668–1677 (2003). https://doi.org/10.1038/sj.onc.1206248
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DOI: https://doi.org/10.1038/sj.onc.1206248
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