Regulation of DNMT1 Stability Through SET7-Mediated Lysine Methylation in Mammalian Cells
Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells Pierre-Olivier Este` vea,1, Hang Gyeong China,1, Jack Bennera, George R. Feeherya, Mala Samaranayakea, Gregory A. Horwitzb, Steven E. Jacobsenb, and Sriharsa Pradhana,2 aNew England Biolabs Incorporated, 240 County Road, Ipswich, MA 01938; and bHoward Hughes Medical Institute and Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095-1606 Edited by Jasper Rine, University of California, Berkeley, CA, and approved February 10, 2009 (received for review October 15, 2008) Inheritance of epigenetic information encoded by cytosine DNA A D methylation patterns is crucial for mammalian cell survival, in large ET7 S part through the activity of the maintenance DNA methyltrans- : IP: IgG IP IP: DNMT1 449 kDa ferase (DNMT1). Here, we show that SET7, a known histone 159 kDa Anti- methyltransferase, is involved in the regulation of protein stability DNMT1 Anti- of DNMT1. SET7 colocalizes and directly interacts with DNMT1 and DNMT1 Anti- specifically monomethylates Lys-142 of DNMT1. Methylated SET7 DNMT1 peaks during the S and G2 phases of the cell cycle and is DsRed- Merged/ prone to proteasome-mediated degradation. Overexpression of B C Time Nucleus DNMT1 SET7 Merged Nucleus SET7 leads to decreased DNMT1 levels, and siRNA-mediated knock- (hrs) down of SET7 stabilizes DNMT1. These results demonstrate that 2-4 SET7 PRMT1 signaling through SET7 represents a means of DNMT1 enzyme G9a DNMT1 turnover. [3H] 4-8 DNA methyltransferase ͉ methylated lysine ͉ proteasome ͉ protein degradation 8-12 H3 H4 ammalian DNA methylation is essential for development Mand is controlled by a variety of factors including 3 active >15 DNA cytosine methyltransferases (DNMT1, DNMT3A, and DNMT3B) and a methyltransferase-like protein, DNMT3L (1– 4).
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