Physical Sciences and Mathematics Commons^™

Methylated Dnmt1 And E2f1 Are Targeted For Proteolysis By L3mbtl3 And Crl4dcaf5 Ubiquitin Ligase, Feng Leng, Jiekai Yu, Chunxiao Zhang, Salvador Alejo, Nam Hoang, Hong Sun, Fei Lu, Hui Zhang

Chemistry and Biochemistry Faculty Research

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. …