Abstract
Many non-histone proteins are lysine methylated and a novel function of this modification is to trigger the proteolysis of methylated proteins. Here, we report that the methylated lysine 142 of DNMT1, a major DNA methyltransferase that preserves epigenetic inheritance of DNA methylation patterns during DNA replication, is demethylated by LSD1. A novel methyl-binding protein, L3MBTL3, binds the K142-methylated DNMT1 and recruits a novel CRL4DCAF5 ubiquitin ligase to degrade DNMT1. Both LSD1 and PHF20L1 act primarily in S phase to prevent DNMT1 degradation by L3MBTL3-CRL4DCAF5. Mouse L3MBTL3/MBT-1 deletion causes accumulation of DNMT1 protein, increased genomic DNA methylation, and late embryonic lethality. DNMT1 contains a consensus methylation motif shared by many non-histone proteins including E2F1, a key transcription factor for S phase. We show that the methylation-dependent E2F1 degradation is also controlled by L3MBTL3-CRL4DCAF5. Our studies elucidate for the first time a novel mechanism by which the stability of many methylated non-histone proteins are regulated.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Animals
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DNA (Cytosine-5-)-Methyltransferase 1 / chemistry
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DNA (Cytosine-5-)-Methyltransferase 1 / genetics*
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DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
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DNA Methylation
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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E2F1 Transcription Factor / genetics*
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E2F1 Transcription Factor / metabolism
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Female
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Gene Deletion
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Histone Demethylases / genetics
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Histone Demethylases / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Male
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Methylation
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Mice
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Protein Binding
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Protein Stability
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Proteolysis
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Ubiquitin-Protein Ligase Complexes / genetics
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Ubiquitin-Protein Ligase Complexes / metabolism*
Substances
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DNA-Binding Proteins
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Dcaf5 protein, mouse
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E2F1 Transcription Factor
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E2f1 protein, mouse
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Intracellular Signaling Peptides and Proteins
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MBT-1 protein, mouse
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Histone Demethylases
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KDM1a protein, mouse
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DNA (Cytosine-5-)-Methyltransferase 1
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Dnmt1 protein, mouse
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Ubiquitin-Protein Ligase Complexes
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CRL4 E3 ubiquitin ligase complex, mouse