CRL4VprBP E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases

Tadashi Nakagawa, Lei Lv, Makiko Nakagawa, Yanbao Yu, Chao Yu, Ana C. D'Alessio, Keiko Nakayama, Heng Yu Fan, Xian Chen, Yue Xiong

Research output: Contribution to journalArticlepeer-review

86 Citations (Scopus)


DNA methylation at the C-5 position of cytosine (5mC) regulates gene expression and plays pivotal roles invarious biological processes. The TET dioxygenases catalyze iterative oxidation of 5mC, leading toeventual demethylation. Inactivation of TET enzymes causes multistage developmental defects, impaired cell reprogramming, and hematopoietic malignancies. However, little is known about how TET activity is regulated. Here we show that all three TET proteins bind to VprBP and are monoubiquitylated by the VprBP-DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4VprBP) on a highly conserved lysine residue. Deletion of VprBP in oocytes abrogated paternal DNA hydroxymethylation in zygotes. VprBP-mediated monoubiquitylation promotes TET binding to chromatin. Multiple recurrent TET2-inactivating mutations derived from leukemia target either the monoubiquitylation site (K1299) or residues essential for VprBP binding. Cumulatively, our data demonstrate that CRL4VprBP is a critical regulator of TET dioxygenases during development and in tumor suppression.

Original languageEnglish
Pages (from-to)247-260
Number of pages14
JournalMolecular Cell
Issue number2
Publication statusPublished - 2015 Jan 22


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