Methylated Proteins are Targeted for Proteolysis by L3MBTL3 and CRL4-DCAF5 Ubiquitin E3 ligase

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Molecular Cell


Lysine methylation is a major protein modification and emerging evidence indicates that many non-histone proteins are methylated to regulate their activity or protein stability. How the methylated non-histone proteins are recognized and processed remains largely unclear. Here we show that the methylated lysine residue that triggers the proteolysis of DNMT1, a major DNA methyltransferase that preserves epigenetic inheritance of DNA methylation patterns during DNA replication, is recognized by the Malignant Brain Tumor (MBT) domain of L3MBTL3 in a cell cycle-dependent manner. L3MBTL3 further interacts with the CRL4-DCAF5 ubiquitin ligase to target DNMT1 for proteolysis. Since the consensus methylation motif in DNMT1 is present in many non-histone proteins including E2F1, a key transcription factor for S-phase, we show that the methylation-dependent degradation of E2F1 is also controlled by the CRL4-DCAF5-L3MBTL3 complexes. Our studies thus reveal a novel and common mechanism by which the stability of many methylated non-histone proteins are regulated.



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