A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability
| Autor: | Xiaodong Cheng, Pierre Olivier Estève, Anup K. Upadhyay, George R. Feehery, John R. Horton, Sriharsa Pradhan, Mala Samaranayake, Yanqi Chang |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Models Molecular inorganic chemicals Biology Crystallography X-Ray Methylation environment and public health Article Structural Biology Histone methylation Serine Humans Histone code DNA (Cytosine-5-)-Methyltransferases Phosphorylation Molecular Biology Epigenomics Genome Human Protein Stability urogenital system Lysine Histone-Lysine N-Methyltransferase DNA Methylation Protein Structure Tertiary DNA demethylation Biochemistry Histone methyltransferase embryonic structures DNA methylation Proto-Oncogene Proteins c-akt |
| Zdroj: | Nature Structural & Molecular Biology. 18:42-48 |
| ISSN: | 1545-9985 1545-9993 |
| DOI: | 10.1038/nsmb.1939 |
| Popis: | The protein lysine methyltransferase SET7 regulates DNA methyltransferase-1 (DNMT1) activity in mammalian cells by promoting degradation of DNMT1 and thus allows epigenetic changes via DNA demethylation. Here we reveal an interplay between monomethylation of DNMT1 Lys142 by SET7 and phosphorylation of DNMT1 Ser143 by AKT1 kinase. These two modifications are mutually exclusive, and structural analysis suggests that Ser143 phosphorylation interferes with Lys142 monomethylation. AKT1 kinase colocalizes and directly interacts with DNMT1 and phosphorylates Ser143. Phosphorylated DNMT1 peaks during DNA synthesis, before DNMT1 methylation. Depletion of AKT1 or overexpression of dominant-negative AKT1 increases methylated DNMT1, resulting in a decrease in DNMT1 abundance. In mammalian cells, phosphorylated DNMT1 is more stable than methylated DNMT1. These results reveal cross-talk on DNMT1, through modifications mediated by AKT1 and SET7, that affects cellular DNMT1 levels. |
| Databáze: | OpenAIRE |
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