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

• Published in: Nature communications 2018-03, Vol.9 (1), p.1017-16, Article 1017
• Main Authors: Borisova, Marina E., Voigt, Andrea, Tollenaere, Maxim A. X., Sahu, Sanjeeb Kumar, Juretschke, Thomas, Kreim, Nastasja, Mailand, Niels, Choudhary, Chunaram, Bekker-Jensen, Simon, Akutsu, Masato, Wagner, Sebastian A., Beli, Petra
• Format: Article
• Language: English
• Subjects: 14-3-3 protein; 14-3-3 Proteins - metabolism; 45/15; 631/337/1427/2566; 631/337/1645; 631/337/458/1733; 631/337/475; 82/58; Ataxia Telangiectasia Mutated Proteins - metabolism; Binding; Cell Line, Tumor; Chromatin; Chromatin - metabolism; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA-Binding Proteins - metabolism; DNA-directed RNA polymerase; Elongation; HEK293 Cells; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Light; MAP kinase; Metabolism; multidisciplinary; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Protein kinase; Protein-Serine-Threonine Kinases - metabolism; Proteins; Radiation damage; Ribonucleic acid; RNA; RNA - metabolism; RNA polymerase II; RNA Polymerase II - metabolism; RNA-binding protein; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Serine; Signal transduction; Signal Transduction - genetics; Signaling; Splicing; Substrates; Transcription; Transcription Factors - metabolism; Ultraviolet radiation; Ultraviolet Rays - adverse effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03417-3

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. UV-light-induced DNA damage affects RNA metabolism but the underlying signalling pathways are largely unexplored. Here, the authors show that UV light triggers p38-MK2-mediated phosphorylation of the NELF complex, promoting its release from chromatin and concurrent transcriptional elongation.