title: CRL4(VprBP) E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Lv
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Makiko
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Yanbao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: D'Alessio
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
authors.forename: Heng-Yu
authors.initials: HY
authors.lastname: Fan
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.|Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D020134:Catalytic Domain; D002843:Chromatin / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; D044767:Ubiquitin-Protein Ligases; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases