Despite being discovered nearly 40 years ago, the significance of circular RNA (circRNA) has only recently been recognized. Once thought to represent errors in splicing, circRNAs are now known to play a key role in gene regulation.
Structure and function of circular RNA
Typically formed via backsplicing of exons and introns, circRNAs are classified covalently linked non-coding RNAs resulting in a circular shape.
This sets them apart from linear RNAs which have 3’ and 5’ ends. Their unique shape enables them to avoid degradation by RNA exonucleases and contributes to their abundance and stability in the cytoplasm of eukaryotic cells.
Emerging evidence suggests that circRNAs can act as therapeutic targets or vectors to treat cancer and act as disease biomarkers.
Classification of CircRNA
More than 30,000 types of circRNAs have been identified. The diversity among them is vast, and it is expected that the number of newly discovered circRNAs will steadily grow.
Found ubiquitously, the expression of specific circRNAs is known to change at various developmental stages. They are known to have a role in disease development, progression and the regulation of disease states.
CircRNA can be categorised into 3 groups:
- Intronic CircRNA (ciRNA)
- Exonic circRNA (ecRNA)
- Exon-intron CircRNA (ElciRNA)
Both ciRNA AND ecRNA are resistant to RNase R. While ecRNA is found in the cytoplasm, ciRNA are located in cell nuclei and are made up of introns derived from linear RNA.
EcRNAs are found in pre-mRNA during the process of exons skipping. Like ciRNA, ElciRNA are located the nuclei of cells and originate from both introns and exons.
Biological functions of CircRNA
CircRNA are known as micro RNA (miRNA) sponges due to their ability to bind to miRNA molecules and influence their function. They play a key role in the regulating miRNA target genes.
Due their stability, circRNA can also act as protein decoys, bind and interact with a multitude of proteins. CircRNAs are transcriptional regulators and can be translated. Depletion of ciRNAs in cell nuclei leads to reduced transcription of several genes (including sirt7, mcm5 and ankrd52).
CircRNA in the cardiovascular system
In 2015, 31% of global deaths were related to cardiovascular disease. Despite the fact that non-coding RNAs such as microRNAs and LncRNAs have been investigated as potential therapeutic targets to treat CVD, there is little evidence to discern if circRNAs could have similar implications.
A recent study has identified a circRNA, MICRA, to be associated with the development of heart failure in patients with acute myocardial infarction. It was also observed that incremental increases in MICRA were associated with the increased risk of adverse events in patients.
CircRNA as an individualized approach to cancer treatment
Discerning the differences in biomarkers expressed in cancerous and normal tissue is an essential aspect of the development of new therapeutic targets. Though the study of circRNAs in cancer biology is still in its infancy, the potential use of circRNAs as biomarkers is growing area of research.
Future prospects for CircRNA
The discovery of new circRNAs can be aided by the use of databases which use predictive algorithms. The databases can also predict the function of specific circRNAS enabling circRNAS to be associated with disease states.
The regulatory role played by circRNAs would be better understood if the mechanisms behind circRNA biogenesis were fully characterised.
As circRNA research is relatively new, the future work into their potential seems promising and should garner interesting insights into their use as biomarkers and therapeutic targets.