A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability

被引：168

作者：

Esteve, Pierre-Olivier ^{[1
]}

Chang, Yanqi ^{[2
]}

Samaranayake, Mala ^{[1
]}

Upadhyay, Anup K. ^{[2
]}

Horton, John R. ^{[2
]}

Feehery, George R. ^{[1
]}

Cheng, Xiaodong ^{[2
]}

Pradhan, Sriharsa ^{[1
]}

机构：

[1] New England Biolabs Inc, Ipswich, MA USA

[2] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2011年 / 18卷 / 01期

基金：

美国国家卫生研究院;

关键词：

DNA CYTOSINE-5 METHYLTRANSFERASE; DE-NOVO; MAINTENANCE; SPECIFICITY; COMPLEX; TARGET; P53;

D O I：

10.1038/nsmb.1939

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：42 / +

页数：8

共 40 条

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