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RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-{kappa}B pathway

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Official URL:https://doi.org/10.1038/ncomms8367
PubMed:View item in PubMed
Creators Name:Murakawa, Y. and Hinz, M. and Mothes, J. and Schuetz, A. and Uhl, M. and Wyler, E. and Yasuda, T. and Mastrobuoni, G. and Friedel, C.C. and Doelken, L. and Kempa, S. and Schmidt-Supprian, M. and Bluethgen, N. and Backofen, R. and Heinemann, U. and Wolf, J. and Scheidereit, C. and Landthaler, M.
Journal Title:Nature Communications
Journal Abbreviation:Nat Commun
Volume:6
Page Range:7367
Date:14 July 2015
Keywords:Binding Sites, DNA Damage, DNA-Binding Proteins, Gene Expression Regulation, Gene Knockdown Techniques, HEK293 Cells, I-{kappa} B Proteins, Intracellular Signaling Peptides and Proteins, Messenger RNA, NF-{kappa} B, Nuclear Proteins, Polyacrylamide Gel Electrophoresis, Post-Transcriptional RNA Processing, RNA Stability, RNA-Binding Proteins, Signal Transduction, Ubiquitin-Protein Ligases, Western Blotting
Abstract:The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNF{alpha} 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-{kappa}B pathway regulators such as I{kappa}B{alpha} 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-{kappa}B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-{kappa}B pathway.
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Item Type:Article

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