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

Yasuhiro Murakawa, Michael Hinz, Janina Mothes, Anja Schuetz, Michael Uhl, Emanuel Wyler, Tomoharu Yasuda, Guido Mastrobuoni, Caroline C. Friedel, Lars Dölken, Stefan Kempa, Marc Schmidt-Supprian, Nils Blüthgen, Rolf Backofen, Udo Heinemann, Jana Wolf, Claus Scheidereit, Markus Landthaler

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51 Citations (Scopus)

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-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.

Original languageEnglish
Article number7367
JournalNature communications
Volume6
DOIs
Publication statusPublished - Jul 14 2015

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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