CRL4(VprBP) E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases

Mol Cell. 2015 Jan 22;57(2):247-260. doi: 10.1016/j.molcel.2014.12.002. Epub 2014 Dec 31.


DNA methylation at the C-5 position of cytosine (5mC) regulates gene expression and plays pivotal roles in various biological processes. The TET dioxygenases catalyze iterative oxidation of 5mC, leading to eventual 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 (CRL4(VprBP)) 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 CRL4(VprBP) is a critical regulator of TET dioxygenases during development and in tumor suppression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / physiology*
  • Catalytic Domain
  • Chromatin / enzymology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation, Missense
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Ubiquitin-Protein Ligases
  • Ubiquitination*


  • Carrier Proteins
  • Chromatin
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Dioxygenases
  • TET2 protein, human
  • Ubiquitin-Protein Ligases
  • DCAF1 protein, human
  • Protein Serine-Threonine Kinases