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

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  • Feng Leng

    (University of Nevada
    Peking University Shenzhen Graduate School)

  • Jiekai Yu

    (University of Nevada)

  • Chunxiao Zhang

    (University of Nevada
    Peking University Shenzhen Graduate School)

  • Salvador Alejo

    (University of Nevada)

  • Nam Hoang

    (University of Nevada)

  • Hong Sun

    (University of Nevada)

  • Fei Lu

    (Peking University Shenzhen Graduate School)

  • Hui Zhang

    (University of Nevada)

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.

Suggested Citation

  • Feng Leng & Jiekai Yu & Chunxiao Zhang & Salvador Alejo & Nam Hoang & Hong Sun & Fei Lu & Hui Zhang, 2018. "Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04019-9
    DOI: 10.1038/s41467-018-04019-9
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    Cited by:

    1. Ji Min Lee & Henrik M. Hammarén & Mikhail M. Savitski & Sung Hee Baek, 2023. "Control of protein stability by post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Pengfei Guo & Nam Hoang & Joseph Sanchez & Elaine H. Zhang & Keshari Rajawasam & Kristiana Trinidad & Hong Sun & Hui Zhang, 2022. "The assembly of mammalian SWI/SNF chromatin remodeling complexes is regulated by lysine-methylation dependent proteolysis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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