Abstract
Simple SummaryThe role of non-coding RNA, and particularly of circular RNA, in the DNA damage response and repair network is underappreciated. Given the vital role of this network in preserving the genomic integrity and consequently cellular homeostasis, the constantly increasing numbers of discovered circular RNAs and the increasing implication of these molecules in the function of this network unravel a new important field that may open new therapeutic opportunities, but also require detailed investigation.Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been discovered, the majority still remains poorly characterized. Particularly, there is no detailed information on the identity and functional role of circRNAs that are transcribed from genes encoding components of the DNA damage response and repair (DDRR) network. In this article, we not only review the available published information on DDRR-related circRNAs, but also conduct a bioinformatic analysis on data obtained from public repositories to uncover deposited, yet uncharacterized circRNAs derived from components of the DDRR network. Finally, we interrogate for potential targets that are regulated by this class of molecules and look into potential functional implications.
Highlights
Chromosomal rearrangements following incorrect repair of DNA double-strand breaks (DSB) constitute one of the primary causes of tumorigenesis, setting the grounds for genomic instability [1]
This database encompasses public circRNA datasets obtained from NGS of transcriptome from various tissues and mainly cell lines, which were processed for the potential presence of circular RNAs derived from back-splicing events from the genes of interest
Given that the damage response and repair (DDRR) network is vast, consisting of many components [2], we focused mainly on the following core components; NBS1, MRE11 and RAD50 that form the MRN adaptor complex; TP53BP1, a factor involved in tipping the balance between Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ) DNA repair routes; the apical Ataxia-Telangiectasia Mutated (ATM), ATR and downstream CHK1/CHK2 kinases, and TP53, a key downstream DDRR effector [2] (Figures 2–6 and Supplementary Figure S1)
Summary
Chromosomal rearrangements following incorrect repair of DNA double-strand breaks (DSB) constitute one of the primary causes of tumorigenesis, setting the grounds for genomic instability [1]. CircRNAs are produced by exons or lariat introns by a process called back-splicing, whereby the 3 and 5 ends normally encountered in an RNA molecule are covalently joined together in a circular structure (Figure 1) [12,13] Through their cis and trans functions, circRNAs have been found to regulate important oncogenes and tumor suppressors, including major players of the DDRR network [10]. An emerging body of evidence suggests that circRNAs may act as ceRNAs to regulate important biological properties related to tumorigenesis, such as proliferation, angiogenesis and apoptosis [39] It is, becoming clear that circRNAs are associated with cancer patient clinical outcomes, by exerting important functions in cancer cells [41,42,43]. As circRNAs have been identified in exosomes and body fluids, they hold great promise as novel disease biomarkers [43,47,48]
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