Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase.
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.
Mesh Terms:
Amino Acid Motifs, Animals, DNA (Cytosine-5-)-Methyltransferase 1, DNA Methylation, DNA-Binding Proteins, E2F1 Transcription Factor, Female, Gene Deletion, Histone Demethylases, Humans, Intracellular Signaling Peptides and Proteins, Male, Methylation, Mice, Protein Binding, Protein Stability, Proteolysis, Ubiquitin-Protein Ligase Complexes
Amino Acid Motifs, Animals, DNA (Cytosine-5-)-Methyltransferase 1, DNA Methylation, DNA-Binding Proteins, E2F1 Transcription Factor, Female, Gene Deletion, Histone Demethylases, Humans, Intracellular Signaling Peptides and Proteins, Male, Methylation, Mice, Protein Binding, Protein Stability, Proteolysis, Ubiquitin-Protein Ligase Complexes
Nat Commun
Date: Dec. 24, 2017
PubMed ID: 29691401
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