The circRNA interactome–innovative hallmarks of the intra- and extracellular radiation response

// Valerie Brid O'Leary 1 , Jan Smida 1 , Martina Matjanovski 1 , Corinna Brockhaus 1 , Klaudia Winkler 1 , Simone Moertl 1 , Saak Victor Ovsepian 2, 3 and Michael John Atkinson 1, 4 1 Institute of Radiation Biology, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Neuherberg, Germany 2 Institute of Biological and Medical Imaging, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Neuherberg, Germany 3 Faculty for Electrical Engineering and Information Technology, Technical University Munich, Munich, Germany 4 Chair of Radiation Biology, Technical University Munich, Munich, Germany Correspondence to: Valerie Brid O'Leary, email: olearyv@yahoo.co.uk Keywords: circRNA, WWOX, QUAKING, KIRKOS, exosomes Received: May 07, 2017      Accepted: June 10, 2017      Published: July 13, 2017 ABSTRACT Generated by Quaking (QKI), circular RNAs (circRNAs) are newly recognised non-coding RNA (ncRNA) members characterised by tissue specificity, increased stability and enrichment within exosomes. Studies have shown that ionizing radiation (IR) can influence ncRNA transcription. However, it is unknown whether circRNAs or indeed QKI are regulated by IR. Microarray circRNA profiling and next generation sequencing revealed that circRNA expression was altered by low and medium dose exposure sourced predominantly from genes influencing the p53 pathway. CircRNAs KIRKOS-71 and KIRKOS-73 transcribed from the WWOX ( WW Domain Containing Oxidoreductase ) tumor suppressor (a p53 regulator) responded within hours to IR. KIRKOS-71 and KIRKOS-73 were present in exosomes yet exhibited differential transcript clearance between irradiated cell lines. Dual-quasar labelled probes and in-situ hybridization demonstrated the intercellular distribution of KIRKOS-71 and KIRKOS-73 predominantly within the perinucleus. QKI knockdown removed nuclear expression of these circRNAs with no significant effect on cytosolic KIRKOS-71 and KIRKOS-73. Distinct QKI transcription between cell lines and its augmented interaction with KIRKOS-71 and KIRKOS-73 was noted post IR. This foremost study provides evidence that QKI and circRNAs partake in the cellular irradiation response. KIRKOS-71 and KIRKOS-73 as stable secreted circRNAs may afford vital characteristics worth syphoning as promising diagnostic radiotherapy biomarkers.