Back to Search
Start Over
CRL4(VprBP) E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases.
- Source :
-
Molecular cell [Mol Cell] 2015 Jan 22; Vol. 57 (2), pp. 247-260. Date of Electronic Publication: 2014 Dec 31. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Animals
Catalytic Domain
DNA-Binding Proteins genetics
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
Ubiquitin-Protein Ligases
Carrier Proteins physiology
Chromatin enzymology
DNA-Binding Proteins metabolism
Proto-Oncogene Proteins metabolism
Ubiquitination
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 57
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 25557551
- Full Text :
- https://doi.org/10.1016/j.molcel.2014.12.002