TY - JOUR
T1 - RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κ B pathway
AU - Murakawa, Yasuhiro
AU - Hinz, Michael
AU - Mothes, Janina
AU - Schuetz, Anja
AU - Uhl, Michael
AU - Wyler, Emanuel
AU - Yasuda, Tomoharu
AU - Mastrobuoni, Guido
AU - Friedel, Caroline C.
AU - Dölken, Lars
AU - Kempa, Stefan
AU - Schmidt-Supprian, Marc
AU - Blüthgen, Nils
AU - Backofen, Rolf
AU - Heinemann, Udo
AU - Wolf, Jana
AU - Scheidereit, Claus
AU - Landthaler, Markus
N1 - Funding Information:
We thank all members of the Landthaler laboratory for helpful discussion and critical reading of the manuscript. We thank Dr Nikolaus Rajewsky (MDC) and members of his laboratory for sharing the PAR-CLIP computational analysis pipeline. Dr Markus Schueler (MDC) for initial PAR-CLIP analysis, Ouidad Benlasfer (MDC) and Charlotte Stein for technical assistance, and Claudia Langnick and Mirjam Feldkamp from Dr Wei Chen laboratory (MDC) for sequencing. The Protein Sample Production Facility at the Max Delbrück Center is funded by the Helmholtz Association of German Research Centres. C.S. and J.W. are supported in part by the Federal Ministry for Education and Research (BMBF) CancerSys project 0316047A. As part of the Berlin Institute for Medical Systems Biology at the MDC, the research group of M.L. is funded by the BMBF and the Senate of Berlin, Berlin, Germany. M.S.-S. is supported by SCH2440/3–1. Y.M. is funded by the Deutsche Akademische Austauschdienst.
PY - 2015/7/14
Y1 - 2015/7/14
N2 - 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-κ B pathway regulators such as Iκ Bα 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 Iκ B kinase and NF-κ B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-κ B pathway.
AB - 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-κ B pathway regulators such as Iκ Bα 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 Iκ B kinase and NF-κ B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-κ B pathway.
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U2 - 10.1038/ncomms8367
DO - 10.1038/ncomms8367
M3 - Article
C2 - 26170170
AN - SCOPUS:84937047445
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 7367
ER -