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

Research output: Contribution to journalArticle

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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

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RNA-Binding Proteins
DNA Damage
Binding Sites
proteins
Messenger RNA
RNA Stability
decay
deoxyribonucleic acid
Fingers
damage
Phosphotransferases
DNA
regulators
Proteins

All Science Journal Classification (ASJC) codes

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

Cite this

Murakawa, Y., Hinz, M., Mothes, J., Schuetz, A., Uhl, M., Wyler, E., ... Landthaler, M. (2015). RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κ B pathway. Nature communications, 6, [7367]. https://doi.org/10.1038/ncomms8367

RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κ B pathway. / Murakawa, Yasuhiro; Hinz, Michael; Mothes, Janina; Schuetz, Anja; Uhl, Michael; Wyler, Emanuel; Yasuda, Tomoharu; Mastrobuoni, Guido; Friedel, Caroline C.; Dölken, Lars; Kempa, Stefan; Schmidt-Supprian, Marc; Blüthgen, Nils; Backofen, Rolf; Heinemann, Udo; Wolf, Jana; Scheidereit, Claus; Landthaler, Markus.

In: Nature communications, Vol. 6, 7367, 14.07.2015.

Research output: Contribution to journalArticle

Murakawa, Y, Hinz, M, Mothes, J, Schuetz, A, Uhl, M, Wyler, E, Yasuda, T, Mastrobuoni, G, Friedel, CC, Dölken, L, Kempa, S, Schmidt-Supprian, M, Blüthgen, N, Backofen, R, Heinemann, U, Wolf, J, Scheidereit, C & Landthaler, M 2015, 'RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κ B pathway', Nature communications, vol. 6, 7367. https://doi.org/10.1038/ncomms8367
Murakawa, Yasuhiro ; Hinz, Michael ; Mothes, Janina ; Schuetz, Anja ; Uhl, Michael ; Wyler, Emanuel ; Yasuda, Tomoharu ; Mastrobuoni, Guido ; Friedel, Caroline C. ; Dölken, Lars ; Kempa, Stefan ; Schmidt-Supprian, Marc ; Blüthgen, Nils ; Backofen, Rolf ; Heinemann, Udo ; Wolf, Jana ; Scheidereit, Claus ; Landthaler, Markus. / RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κ B pathway. In: Nature communications. 2015 ; Vol. 6.
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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.",
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