Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase

Nat Commun. 2018 Apr 24;9(1):1641. doi: 10.1038/s41467-018-04019-9.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • DNA (Cytosine-5-)-Methyltransferase 1 / chemistry
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics*
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • E2F1 Transcription Factor / genetics*
  • E2F1 Transcription Factor / metabolism
  • Female
  • Gene Deletion
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Methylation
  • Mice
  • Protein Binding
  • Protein Stability
  • Proteolysis
  • Ubiquitin-Protein Ligase Complexes / genetics
  • Ubiquitin-Protein Ligase Complexes / metabolism*

Substances

  • DNA-Binding Proteins
  • Dcaf5 protein, mouse
  • E2F1 Transcription Factor
  • E2f1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • MBT-1 protein, mouse
  • Histone Demethylases
  • KDM1a protein, mouse
  • DNA (Cytosine-5-)-Methyltransferase 1
  • Dnmt1 protein, mouse
  • Ubiquitin-Protein Ligase Complexes
  • CRL4 E3 ubiquitin ligase complex, mouse