Beyond the 3′UTR binding-microRNA-induced protein truncation via DNA binding

Abstract

// Melanie von Brandenstein 1 , Stephan H. Bernhart 5 , Andreas Pansky 3 , Claudia Richter 2 , Tobias Kohl 1 , Martina Deckert 4 , Axel Heidenreich 1 , Peter F. Stadler 5 , Manuel Montesinos-Rongen 4, * and Jochen W.U. Fries 2, * 1 Department of Urology, University Hospital of Cologne, Cologne, Germany 2 Institute of Pathology, University Hospital of Cologne, Cologne, Germany 3 Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, Rheinbach, Germany 4 Institute of Neuropathology, University Hospital of Cologne, Cologne, Germany 5 Bioinformatics Group, Department of Computer Science and Interdisciplinary Center of Bioinformatics, Leipzig University, Leipzig, Germany * Co-senior authors Correspondence to: Manuel Montesinos-Rongen, email: manuel.montesinos-rongen@uk-koeln.de Melanie von Brandenstein, email: melanie@vonbrandenstein.de Keywords: Vim3; Mxi-2; miR-498; miR-15; DNA interaction Received: May 23, 2018      Accepted: August 04, 2018      Published: August 28, 2018 ABSTRACT Here, we present a miR mechanism which is active in the nucleus and is essential for the production of intron included, C-terminal truncated and biologically active proteins, like e.g. Vim3. We exemplified this mechanism by miRs, miR-15a and miR-498, which are overexpressed in clear cell renal carcinoma or oncocytoma. Both miRs directly interact with DNA in an intronic region, leading to transcriptional stop, and therefore repress the full length version of the pre-mRNA, resulting in intron included truncated proteins (Mxi-2 and Vim3). A computational survey shows that this miR:DNA interactions mechanism may be generally involved in regulating the human transcriptome, with putative interaction sites in intronic regions for over 1000 genes. In this work, an entirely new mechanism is revealed how miRs can repress full length protein translation, resulting in C-terminal truncated proteins.