Linear RNA transcripts are the most common type of RNA molecules found in human cells. A subgroup of functional RNA molecules in a circular structure, called circular RNAs (circRNAs), have been found to contribute to many diseases such as neurological diseases, cardiovascular diseases and cancer when aberrantly expressed. However, the precise mechanisms underlying the regulation of circRNA biogenesis in cells, especially cancer cells, remain unexplored. Now, researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore have taken a step further and identified Adenosine deaminases acting on RNA (ADARs) as potent regulators of circRNAs in a bi-directional manner, through and beyond their RNA editing function. The team’s findings were published in the journal Nature Communications on 21 March 2022.

ADARs-mediated RNA editing is a widespread co- and post-transcriptional modification process which introduces changes in RNA sequences encoded by the genome, thereby contributing to “RNA mutations”. In the past decade, the dysregulated adenosine-to-inosine (A-to-I) RNA editing has been proven to be an important mechanism in cancer development. Helmed by Associate Professor Polly Leilei Chen, the research group hypothesized that ADARs and RNA editing may have implications on circRNA biogenesis. As such, they embarked on the study to better understand the role of crosstalk between RNA editing machinery (ADAR proteins) and circRNA biogenesis machinery in cancer.

The team found that ADARs-mediated A-to-I editing can stabilize or destabilize the circRNA-driving secondary structures formed by flanking non-coding regions of the RNA (introns), via correcting mismatches or creating wobble pairs, respectively. These editing-mediated changes on flanking introns could also affect the binding of RNA binding proteins (RBPs) to regulate circRNA biogenesis. Collectively, ADARs-regulated circRNAs have been found to be ubiquitous in multiple cancers and play critical roles in cancer development.

Findings from this study have advanced the team’s understanding of circRNAs in cancer cells. Their discovery will provide new insights that can contribute to the development of effective therapeutic approaches utilizing ADARs-regulated circRNAs, given their high stability and diverse functions.

Moving forward, the research team will further investigate the specific functions of ADARs-regulated circRNAs in cancer cells. The team also plans to establish the common features of these circRNA species and its functional connection to cancer development, with the aim of identifying potential therapeutic approaches utilizing these circRNAs.