Methylated DNMT1 and E2F1 Are Targeted for Proteolysis by L3MBTL3 and CRL4DCAF5 Ubiquitin Ligase

Authors

Feng Leng, University of Nevada, Las Vegas; Peking University Shenzhen Graduate SchoolFollow
Jiekai Yu, University of Nevada, Las VegasFollow
Chunxiao Zhang, University of Nevada, Las Vegas; Peking University Shenzhen Graduate SchoolFollow
Salvador Alejo, University of Nevada, Las VegasFollow
Nam Hoang, University of Nevada, Las Vegas
Hong Sun, University of Nevada, Las VegasFollow
Fei Lu, Peking University Shenzhen Graduate SchoolFollow
Hui Zhang, University of Nevada, Las VegasFollow

Document Type

Article

Publication Date

4-24-2018

Publication Title

Nature Communications

Volume

9

Issue

1

First page number:

1

Last page number:

17

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.

Keywords

DNA methylation; Ubiquitin ligases

Disciplines

Chemistry

File Format

application/pdf

File Size

2.147 Kb

Language

English

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Repository Citation

Leng, F., Yu, J., Zhang, C., Alejo, S., Hoang, N., Sun, H., Lu, F., Zhang, H. (2018). Methylated DNMT1 and E2F1 Are Targeted for Proteolysis by L3MBTL3 and CRL4DCAF5 Ubiquitin Ligase. Nature Communications, 9(1), 1-17.
http://dx.doi.org/10.1038/s41467-018-04019-9