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.
Feng Leng  1  2 ,  Jiekai Yu  1 ,  Chunxiao Zhang  1  2 ,  Salvador Alejo  1 ,  Nam Hoang  1 ,  Hong Sun  1 ,  Fei Lu  2 ,  Hui Zhang  3
Affiliations
  • 1. Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV89154, USA.
  • 2. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 3. Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV89154, USA. [email protected].
PMID: 29691401 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.