Label-free protein-RNA interactome analysis identifies khsrp signaling downstream of the p38/Mk2 kinase complex as a critical modulator of cell cycle progression

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Abstract

Growing evidence suggests a key role for RNA binding proteins (RBPs) in genome stability programs. Additionally, recent developments in RNA sequencing technologies, as well as mass-spectrometry techniques, have greatly expanded our knowledge on protein-RNA interactions. We here use full transcriptome sequencing and label-free LC/MS/MS to identify global changes in protein-RNA interactions in response to etoposide-induced genotoxic stress. We show that RBPs have distinct binding patterns in response to genotoxic stress and that inactivation of the RBP regulator module, p38/MK2, can affect the entire spectrum of protein-RNA interactions that take place in response to stress. In addition to validating the role of known RBPs like Srsf1, Srsf2, Elavl1 in the genotoxic stress response, we add a new collection of RBPs to the DNA damage response. We identify Khsrp as a highly regulated RBP in response to genotoxic stress and further validate its role as a driver of the G<inf>1</inf>/S transition through the suppression of Cdkn1a<sup>P21</sup> transcripts. Finally, we identify KHSRP as an indicator of overall survival, as well as disease free survival in glioblastoma multiforme.

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Boucas, J., Fritz, C., Schmitt, A., Riabinska, A., Thelen, L., Peifer, M., … Reinhardt, H. C. (2015). Label-free protein-RNA interactome analysis identifies khsrp signaling downstream of the p38/Mk2 kinase complex as a critical modulator of cell cycle progression. PLoS ONE, 10(5). https://doi.org/10.1371/journal.pone.0125745

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