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

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

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.

U2 - 10.1038/s41467-018-03417-3

DO - 10.1038/s41467-018-03417-3

M3 - Journal article

C2 - 29523821

SN - 2041-1723

VL - 9

SP - 1

EP - 16

JO - Nature Communications

JF - Nature Communications

M1 - 1017

ER -