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Nat Commun. 2018 Mar 9;9(1):1017. doi: 10.1038/s41467-018-03417-3.

p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage.

Author information

1
Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany.
2
Cellular Stress Signaling Group, Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3C, 2200, Copenhagen, Denmark.
3
Ubiquitin Signaling Group, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
4
Proteomics and Cell Signaling Group, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
5
Institute of Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt and Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University, Max-von Laue-Strasse 15, 60438, Frankfurt, Germany.
6
Department of Medicine, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
7
German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
8
German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
9
Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany. p.beli@imb-mainz.de.

Abstract

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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PMID:
29523821
PMCID:
PMC5845016
DOI:
10.1038/s41467-018-03417-3
[Indexed for MEDLINE]
Free PMC Article

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