Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV89154, USA.
School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
Nat Commun. 2018 Apr 24;9(1):1641. doi: 10.1038/s41467-018-04019-9.
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 CRL4 ubiquitin ligase to degrade DNMT1. Both LSD1 and PHF20L1 act primarily in S phase to prevent DNMT1 degradation by L3MBTL3-CRL4. 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-CRL4. Our studies elucidate for the first time a novel mechanism by which the stability of many methylated non-histone proteins are regulated.
许多非组蛋白蛋白质都被赖氨酸甲基化，这种修饰的一个新功能是触发甲基化蛋白质的蛋白水解。在这里，我们报告说，DNMT1 中的赖氨酸 142 被 LSD1 去甲基化，DNMT1 是一种主要的 DNA 甲基转移酶，在 DNA 复制过程中保持 DNA 甲基化模式的表观遗传遗传。一种新的甲基结合蛋白 L3MBTL3 结合 K142 甲基化的 DNMT1，并募集一种新型 CRL4 泛素连接酶来降解 DNMT1。LSD1 和 PHF20L1 主要在 S 期发挥作用，以防止 L3MBTL3-CRL4 降解 DNMT1。小鼠 L3MBTL3/MBT-1 缺失导致 DNMT1 蛋白积累、基因组 DNA 甲基化增加和胚胎晚期致死。DNMT1 包含一个共识的甲基化基序，该基序被许多非组蛋白蛋白质共享，包括 E2F1，E2F1 是 S 期的关键转录因子。我们表明，依赖于甲基化的 E2F1 降解也受 L3MBTL3-CRL4 控制。我们的研究首次阐明了许多甲基化非组蛋白蛋白质稳定性受调控的一种新机制。
