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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 and Landthaler, Markus (2015): RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-kappa B pathway. In: Nature Communications, Vol. 6, 7367 [PDF, 3MB]

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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 similar to 3, 800 mRNA targets with 416, 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 30UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with I kappa B kinase and NF-kappa B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-kappa B pathway.

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