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Nat Commun. 2015 Jul 14;6:7367. doi: 10.1038/ncomms8367.

RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway.

Author information

1
RNA Biology and Posttranscriptional Regulation, Berlin Institute of Medical Systems Biology at the Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
2
Signal Transduction in Tumor Cells, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
3
Mathematical Modelling of Cellular Processes, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
4
1] Macromolecular Structure and Interaction, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany [2] Helmholtz Protein Sample Production Facility, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
5
Department of Computer Science and Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-Universität Freiburg, 79110 Freiburg, Germany.
6
Immune Regulation and Cancer, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
7
Integrative Proteomics and Metabolomics Platform, Berlin Institute of Medical Systems Biology at the Max-Delbrück Center for Molecular, 13125 Berlin, Germany.
8
Institut für Informatik, Ludwig-Maximilians-Universität, 80333 München, Germany.
9
Institute for Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany.
10
Department of Hematology and Oncology, Technische Universität, 81675 München, Germany.
11
1] Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany [2] Integrative Research Institute (IRI) for the Life Sciences and Institute for Theoretical Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
12
1] Macromolecular Structure and Interaction, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany [2] Chemistry and Biochemistry Institute, Freie Universität Berlin, 14195 Berlin, Germany.

Abstract

The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNFα mRNA decay via a 3'UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ∼ 3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-κB pathway regulators such as IκBα and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3'UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with IκB kinase and NF-κB activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-κB pathway.

PMID:
26170170
PMCID:
PMC4510711
DOI:
10.1038/ncomms8367
[Indexed for MEDLINE]
Free PMC Article

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