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A new mode of transcriptional repression by c-myc: methylation

Oncogene volume 25, pages 1989–1990 (2006)Cite this article

The proto-oncogene c-myc is a central regulator of cellular proliferation and cell growth, which executes its multiple activities mostly through transcriptional regulation of its target genes. Although the role of c-myc in the activation of transcription is clearly established, the mechanisms of transcriptional repression by c-myc are not well understood. It has been proposed that c-myc represses gene transcription by at least two distinct mechanisms (Gartel and Shchors, 2003). One mechanism is limited to the binding of c-myc to the DNA-binding protein Miz-1, via its C-terminal domain, resulting in inhibition of Miz-1 transcriptional activity (Staller et al., 2001). The other mechanism is dependent on c-myc binding to the Sp1 transcription factor through its central region leading to inhibition of Sp1 transcriptional activity (Gartel et al., 2001). Interestingly, both Sp1 and Miz-1 bind to the proximal promoter of the p21 gene (Gartel et al., 2001; Seoane et al., 2002), which is a major target of Myc repression (Coller et al., 2000).

A new twist was added recently to this picture by Brenner et al. (2005), who suggested that c-myc may also repress transcription by recruitment of a DNA methyltransferase corepressor Dnmt3a. DNA methylation is the most important epigenetic modification in mammalian cells and it is associated with transcriptional repression. Three active DNA CpG methyltransferases, Dnmt1, Dnmt3a, and Dnmt3b, have been identified in mammals (Okano et al., 1998). Dnmt3a and Dnmt3b are required for de novo methylation (Okano et al., 1999) and they can act as corepressors to silence gene expression (Fuks, 2001). Using GST pull-down and co-immunoprecipitation experiments, Brenner et al. showed that Myc interacts with the corepressor Dnmt3a and associates with DNA methyltransferase activity. Since p21 is a well-characterized target of Myc repression (Gartel and Radhakrishnan, 2005), they decided to check if Dnmt3a could act together with Myc to silence p21 gene expression. They found that cotransfection of Myc along with Dnmt3a provided a synergistic repressive effect on p21 promoter-reporter expression. In addition, treatment of U2OS cells with Dnmt3a antisense oligonucleotide led to depletion of Dnmt3a mRNA and protein levels and to induction of p21 mRNA, indicating that Dnmt3a may repress endogenous p21 gene. Using chromatin immunoprecipitation experiments (ChIPs), Brenner et al. demonstrated that Dnmt3a could bind to the proximal p21 promoter only in the presence of Myc, suggesting that Myc is targeting Dnmt3a to the p21 promoter.

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  1. Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    A L Gartel

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  1. A L Gartel
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Correspondence to A L Gartel.

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Gartel, A. A new mode of transcriptional repression by c-myc: methylation. Oncogene 25, 1989–1990 (2006). https://doi.org/10.1038/sj.onc.1209101

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