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Science 325 (5936): 90-93

Copyright © 2009 by the American Association for the Advancement of Science

Jmjd6 Catalyses Lysyl-Hydroxylation of U2AF65, a Protein Associated with RNA Splicing

Celia J. Webby,1,* Alexander Wolf,2,* Natalia Gromak,3,* Mathias Dreger,4 Holger Kramer,5 Benedikt Kessler,5 Michael L. Nielsen,6,{dagger} Corinna Schmitz,2 Danica S. Butler,1 John R. Yates, III,7 Claire M. Delahunty,7 Phillip Hahn,8 Andreas Lengeling,8,9 Matthias Mann,6 Nicholas J. Proudfoot,3 Christopher J. Schofield,1,{ddagger},§ Angelika Böttger2,{ddagger},§

Abstract: The finding that the metazoan hypoxic response is regulated by oxygen-dependent posttranslational hydroxylations, which regulate the activity and lifetime of hypoxia-inducible factor (HIF), has raised the question of whether other hydroxylases are involved in the regulation of gene expression. We reveal that the splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 65-kilodalton subunit (U2AF65) undergoes posttranslational lysyl-5-hydroxylation catalyzed by the Fe(II) and 2-oxoglutarate–dependent dioxygenase Jumonji domain-6 protein (Jmjd6). Jmjd6 is a nuclear protein that has an important role in vertebrate development and is a human homolog of the HIF asparaginyl-hydroxylase. Jmjd6 is shown to change alternative RNA splicing of some, but not all, of the endogenous and reporter genes, supporting a specific role for Jmjd6 in the regulation of RNA splicing.

1 Chemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, Oxon OX1 3TA, UK.
2 Department of Biology II, Ludwig-Maximilians-University, Munich, Großhaderner Strasse 2, D-82152 Planegg-Martinsried, Germany.
3 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, Oxon OX1 3RE, UK.
4 Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford, Oxon OX1 3PT, UK.
5 Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, OX3 7BN, UK.
6 Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
7 Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
8 Research Group Infection Genetics, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany.
9 Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, EBVC, Roslin, EH25 9RG, UK.

* These authors contributed equally to the work.

{dagger} Present address: Department of Proteomics, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.

{ddagger} These authors contributed equally to the work.

§ To whom correspondence should be addressed. E-mail: christopher.schofield{at}chem.ox.ac.uk (C.J.S.); boettger{at}zi.biologie.uni-muenchen.de (A.B).

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