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.
Highlights
An awareness for circular RNA in the non-coding transcriptome came to light with elimination of selection bias only for polyadenylated RNA in high-throughput sequencing approaches [1]
The linear WWOX mRNA transcript (linWWOX) transcript was found in the perinuclear region and in the cytosol but to a lesser extent compared to KIRKOS-71 and KIRKOS-73 (Supplementary Figure 4). These results show that the linWWOX is expressed throughout U2OS with a dissimilar distribution pattern to KIRKOS-71 or KIRKOS-73
While the current literature is sparse in descriptive studies of individual circRNAs, we hereby provide the introduction to KIRKOS-71 and KIRKOS-73, two heterogeneous ‘circles’ spliced from WWOX, the p53 stabiliser
Summary
An awareness for circular RNA (circRNA) in the non-coding transcriptome came to light with elimination of selection bias only for polyadenylated RNA (poly A+) in high-throughput sequencing approaches [1]. Representing covalently closed single stranded loops of ~ 100 nucleotides [3] that lack polarities and poly A+ tails [4], circRNA were considered to be merely aberrant splicing by-products until recently. Their stability and specific expression across developmental stages [3] pointed towards the hidden relevance of circRNAs in cellular homeostasis [1, 4, 5]. The exceptionally high stability of such circulating circRNAs has been attributed to the protection provided by exosomes, their specific sequence features or protein binding partners [14]
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