Human Maintenance DNA (Cytosine-5)-Methyltransferase and p53 Modulate Expression of p53-Repressed Promoters

DNA (cytosine-5)-methyltransferase (DNMT) 1 participates in transcriptional repression of genes by methylation-dependent and-independent mechanisms. Here, DNMT1 is shown to bind p53 and colocalize in the nucleus. DNMT1-mediated methylation is stimulated by p53 in vitro. Upon p53 induction, a reporte...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 4; pp. 1000 - 1005
Main Authors Estève, Pierre-Olivier, Chin, Hang Gyeong, Pradhan, Sriharsa, Sharp, Phillip A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 25.01.2005
National Acad Sciences
Subjects
Binding sites
Biochemistry
Biological Sciences
Cell Line
Cell lines
Deoxyribonucleic acid
DNA
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases - physiology
DNA Methylation
Enzymes
Gene expression
Gene Expression Regulation
Gene Silencing
Genes
HCT116 cells
Histones
Humans
Inhibitor of Apoptosis Proteins
Methylation
Microtubule-Associated Proteins - genetics
Neoplasm Proteins
Plasmids
Polymerase chain reaction
Promoter Regions, Genetic
Repression
Tumor Suppressor Protein p53 - physiology
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Summary:DNA (cytosine-5)-methyltransferase (DNMT) 1 participates in transcriptional repression of genes by methylation-dependent and-independent mechanisms. Here, DNMT1 is shown to bind p53 and colocalize in the nucleus. DNMT1-mediated methylation is stimulated by p53 in vitro. Upon p53 induction, a reporter construct containing the antiapoptotic gene survivin promoter, which contains a natural p53 binding site, was methylated in WT HCT116 cells but not in DNMT1 null or p53 null cells. Endogenous survivin gene repression involves cooperation between DNMT1 and p53 and is relieved by introduction of DNMT1- or p53-specific small inhibitory RNA. DNMT1 null cells did not exhibit a significant repressive effect for p53 responsive survivin and cdc25C gene expression compared with the parental cells. Normal human fibroblasts also exhibited similar DNMT1- and p53-mediated methylation of the survivin promoter, suggesting cooperation between p53 and DNMT1 in gene silencing.
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This paper was submitted directly (Track II) to the PNAS office.
To whom correspondence should be addressed. E-mail: pradhan@neb.com.
Abbreviations: DNMT, DNA (cytosine-5)-methyltransferase; PCNA, proliferating cell nuclear antigen; HDAC, histone deacetylase; doxo, doxorubicin; Ad, adenovirus; siRNA, small inhibitory RNA; IP, immunoprecipitation.
Edited by Phillip A. Sharp, Massachusetts Institute of Technology, Cambridge, MA, and approved December 10, 2004
Author contributions: P.-O.E. and H.G.C. performed research; P.-O.E. and S.P. analyzed data; S.P. designed research; and S.P. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0407729102