DNA methyltransferase-3a interacts with p53 and represses p53-mediated gene expression

Abstract

ABBREVIATIONS DNMTsDNA Methyltransferases GST glutathione-S-transferase ACKNOWLEDGEMENTSWe thank Drs.Tom Shenk for GST-p53 fusion constructs, Chih-Lin Hsieh for Dnmt3a and the Dnmt3am expression constructs, and Bert Vogelstein for the WWP-luciferase construct. This research was partly supported by Grants from Department of Defense (DAMD17-02-1-0619) and the NIH (P30 ES06639 and RO1 CA89526). Research PaperDNA Methyltransferase-3a Interacts with p53 and Represses p53-Mediated Gene Expression ABSTRACTGenome stability maintenance is regulated by both genetic and epigenetic mechanisms. DNA methylation is the predominant epigenetic mechanism in regulation of gene expression and in suppression of mobile DNA elements from random integration in the genome. The importance of DNA methylation in tumorigenesis has been demonstrated in cancer cells, which harbor global genomic DNA hypomethylation and regional hypermethylation at CpG islands of tumor suppressor genes. DNA methylation is mediated by a class of DNA methyltransferases (Dnmts) involved in de novo methylation of genomic DNA and in the maintenance of DNA methylation patterns during replication. Global genomic DNA demethylation induced by 5-Aza-deoxycytidine activates the p53 signaling pathway and induces apoptosis, suggesting that DNA methylation mediated by Dnmts is associated with p53 signaling in maintaining genome stability. In this report, we show that Dnmt3a interacts with p53 directly and represses p53-mediated transactivation of the p21 gene. It was found that trans-repression by Dnmt3a does not require the methyltransferase activity implying that transcriptional repression does not involve promoter silencing through DNA methylation by Dnmt3a. Finally, the activity of Dnmt3a in vivo was demonstrated when this enzyme was overexpressed in a breast cell line in which Dnmt3a repressed p21 upregulation following DNA damage. The results presented in this study provide new understanding of tumor promotion as mediated by Dnmt3a through its interaction with p53, and suppression of the p53-mediated transcription of tumor suppressor genes. Given that the expression of Dnmts is increased in certain cancers, it is likely that increased Dnmts could block the transactivation function of p53 following its induction by chemotherapeutic drugs resulting in chemoresistance. The use of a DNA methyltransferase inhibitor would therefore restore the p53 tumor suppression function and the utilization of such an inhibitor in combination with DNA damage agents might be an effective therapy for certain cancers.

DNMT3A mutations in acute myeloid leukemia

“…However, it is possible that R882 mutations alter functions of DNMT3A that are not yet fully understood, including its ability to bind to other proteins involved in transcriptional regulation and localization to chromatin regions containing methylated DNA. [23][24][25][26] In any case, all DNMT3A mutations are associated with poor overall survival, suggesting that they have an important common effect on the potential of AML cells to cause lethal disease.…”

Epigenetic reprogramming as a key contributor to melanocyte malignant transformation

“…Some studies suggest that their overexpression could be responsible for hypermethylation of tumor suppressor promoters in tumor cells, but until now this hypothesis is not clear. [5][6][7] Posttranslational histone modifications, such as acetylation and methylation of lysine residues, have also been defined as epigenetic modifiers and have a crucial role in the control of gene expression. Overall, lysine acetylation is linked to gene activation whereas lysine methylation can be a marker for both gene activation, as in the case of H3K4 trimethylation, or repression, as in the case of H3K27 and H3K9 trimethylation.…”

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

“…LSH, a protein related to the SNF2 family of chromatin-remodeling ATPases, is required for efficient DNA methylation in mammals, especially at centromeric repeats (10,11). Sequence specificity during developmental or lineage choice is thought to result from interactions between DNMT and transcription factors that would target methylation to specific DNA sequences in gene regulatory regions (12)(13)(14)(15).…”