TY - JOUR
T1 - P38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage
AU - Borisova, Marina E.
AU - Voigt, Andrea
AU - Tollenaere, Maxim A.X.
AU - Sahu, Sanjeeb Kumar
AU - Juretschke, Thomas
AU - Kreim, Nastasja
AU - Mailand, Niels
AU - Choudhary, Chunaram
AU - Bekker-Jensen, Simon
AU - Akutsu, Masato
AU - Wagner, Sebastian A.
AU - Beli, Petra
N1 - Funding Information:
We acknowledge the Paul Scherrer Institut, Villigen, Switzerland, for provision of synchrotron radiation beam time at the beamlines PX and PXIII of the SLS, and thank Meitian Wang and Vincent Olieric for assistance. We acknowledge funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant agreement number 283570). The research in P.B.’s group is supported by the German Research Foundation (Emmy Noether Program, BE 5342/1-1 and SFB 1177 on Selective Autophagy) and the Marie Curie Career Integration Grant from the European Commission (630763). S.A.W. is supported by the LOEWE program Ubiquitin Networks (Ub-Net) of the State of Hesse (Germany), the Else Kröner-Fresenius-Stiftung (2015_A124), and the Else Kröner-Forschungskolleg Frankfurt. The research in M.A.’s group is supported by the Leibniz Award (to Ivan Dikic), the Cluster of Excellence “Macromolecular Complexes” (project EXC115), and the Volkswagen Stiftung. The Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (grant agreement NNF14CC0001). We thank Anja Freiwald for assistance with mass spectrometry analysis. Support by the IMB genomics and bioinformatics core facility is gratefully acknowledged.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV-light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here we employ quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA-binding proteins as primary substrates and 14-3-3 as direct readers of p38-MK2-dependent phosphorylation induced by UV light. Mechanistically, we show that MK2 phosphorylates the RNA-binding subunit of the NELF complex NELFE on Serine 115. NELFE phosphorylation promotes the recruitment of 14-3-3 and rapid dissociation of the NELF complex from chromatin, which is accompanied by RNA polymerase II elongation.
AB - Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV-light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here we employ quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA-binding proteins as primary substrates and 14-3-3 as direct readers of p38-MK2-dependent phosphorylation induced by UV light. Mechanistically, we show that MK2 phosphorylates the RNA-binding subunit of the NELF complex NELFE on Serine 115. NELFE phosphorylation promotes the recruitment of 14-3-3 and rapid dissociation of the NELF complex from chromatin, which is accompanied by RNA polymerase II elongation.
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U2 - 10.1038/s41467-018-03417-3
DO - 10.1038/s41467-018-03417-3
M3 - Article
C2 - 29523821
AN - SCOPUS:85043992675
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1017
ER -