Abstract
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.
SUPPLEMENTAL MATERIAL
This work was supported by a grant from National Cancer Institute of Canada. Jerome Torrisani was supported by a fellowship of the Fondation pour la Recherche Médicale (France).
We thank R. Schneider (Department of Microbiology, New York University School of Medicine) and M. Gorospe (Laboratory of Cellular and Molecular Biology, NIH,Baltimore, MD) for kindly providing pFLAG-CMV2-AUF1 (p37, p40, p42, and p45) expression plasmids and pSilencer 2.0-U6/AUF15 constructs, respectively. We also thank G. Schilders andG. J. Pruijn (Department of Biochemistry, Nijmegen, The Netherlands), D. Tollervey (Wellcome Trust Centre for Cell Biology, University of Edinburgh), and W. J. van Venrooij (Department of Biochemistry, Nijmegen, The Netherlands) for providing the hRrp4p-TAP vector and the hRrp4p, hRrp40, hRrp41, hRrp46, and PM-Scl 75 antibodies. We thank Jing Ni Ou and Nadine Provençal for their technical assistance and Costandina Arvanitis for critical reading of the manuscript.
We declare no conflicts of interests.