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p53-Mediated Repression of DNA Methyltransferase 1 Expression by Specific DNA Binding¹

Departments of Biology and Microbiology & Immunology [E. J. P., S. M. T.] and Massey Cancer Center [S. M. T.], Virginia Commonwealth University, Richmond, Virginia 23298, and William and Karen Davidson Laboratory of Brain Tumor Biology, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202 [O. B.]

Cytosine methylation patterns in genomic DNA are significantly altered in cancer, and de novo CpG island methylation has been implicated in tumor suppressor gene silencing. Here we demonstrate a mechanistic link between the p53tumor suppressor gene and control of epigenetic regulation by genomic methylation. Deletion of p53in HCT116 human colon carcinoma cells and primary mouse astrocytes resulted in a 6-fold increase of DNA cytosine methyltransferase 1 (Dnmt1) mRNA and protein, suggesting relief of p53-mediated Dnmt1repression. A p53 consensus binding site in exon 1 of the human Dnmt1gene bound recombinant p53 in vitro and endogenous p53 in vivo in the absence of stimuli that activate p53, implying that p53 controls Dnmt1transcription through direct DNA binding. Interestingly, ionizing radiation or etoposide, both of which stabilize and activate p53, diminished p53 binding in chromatin immunoprecipitation assays, concomitant with a 5-fold increase in Dnmt1 levels. Our findings suggest that activation of p53 reduces binding and relieves transcriptional repression of the Dnmt1gene, whereas loss of p53, a frequent, early event in tumorigenesis, may significantly contribute to aberrant genomic methylation.

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