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 Previous Article

Molecular and Cellular Biology, January 2007, p. 395-410, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.01236-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

AUF1 Cell Cycle Variations Define Genomic DNA Methylation by Regulation of DNMT1 mRNA Stability{triangledown} ,{dagger}

Jerome Torrisani, Alexander Unterberger, Sachin R. Tendulkar, Keisuke Shikimi, and Moshe Szyf*

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada

Received 7 July 2006/ Returned for modification 28 July 2006/ Accepted 22 September 2006

DNA methylation is a major determinant of epigenetic inheritance. DNA methyltransferase 1 (DNMT1) is the enzyme responsible for the maintenance of DNA methylation patterns during cell division, and deregulated expression of DNMT1 leads to cellular transformation. We show herein that AU-rich element/poly(U)-binding/degradation factor 1 (AUF1)/heterogenous nuclear ribonucleoprotein D interacts with an AU-rich conserved element in the 3' untranslated region of the DNMT1 mRNA and targets it for destabilization by the exosome. AUF1 protein levels are regulated by the cell cycle by the proteasome, resulting in cell cycle-specific destabilization of DNMT1 mRNA. AUF1 knock down leads to increased DNMT1 expression and modifications of cell cycle kinetics, increased DNA methyltransferase activity, and genome hypermethylation. Concurrent AUF1 and DNMT1 knock down abolishes this effect, suggesting that the effects of AUF1 knock down on the cell cycle are mediated at least in part by DNMT1. In this study, we demonstrate a link between AUF1, the RNA degradation machinery, and maintenance of the epigenetic integrity of the cell.

* Corresponding author. Mailing address: Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec H3G 1Y6, Canada. Phone: (514) 398-7107. Fax: (514) 398-6690. E-mail: moshe.szyf{at}mcgill.ca.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2007, p. 395-410, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.01236-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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