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 2015 20;10(5):e0125745. Epub 2015 May 20.

Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.

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(1/)S transition through the suppression of Cdkn1a(P21) transcripts. Finally, we identify KHSRP as an indicator of overall survival, as well as disease free survival in glioblastoma multiforme.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125745PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439058PMC
February 2016
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