RNA Editing

RNA molecules are frequently depicted as single strands of nucleotides that are free to float around inside of cells. This is in stark contrast to the DNA molecule, which is known for its characteristic double-helix structure. Peter Beal, who studies the enzyme at the University of California, Davis, and is working with ProQR on RNA editing therapies, explains that occasionally a portion of an RNA strand can loop back and pair with itself, forming a double-stranded landing pad for ADAR. Peter Beal is collaborating with ProQR on the development of RNA editing therapies. An A-to-I edit is what researchers call the process that occurs when ADAR converts an adenosine at that site into an unusual base called inosine. Because our cellular machinery then interprets the inosine as the more common base guanosine when making proteins from mRNA, the end result of ADAR’s reaction is an A-to-G edit. This is because guanosine is more common than inosine.

The posttranscriptional modification of an RNA nucleotide sequence at one or more positions is referred to as abstract RNA 

editing. There are two primary categories of RNA editing, namely, substitution editing and insertion/deletion editing. Substitution editing is the more common type. Editing of RNA in either of its two forms will result in the production of transcripts with sequences that are distinct from those of the genome template. One form of genetic recording is represented by the presence of such RNA sequence differences between the mature transcript and the encoding genome. During the process of mRNA biogenesis in eukaryotes, additional RNA processing events such as 5′-capping, 3′-polyadenylation, and splicing take place. The sequence changes that result from RNA editing are distinct from those that result from these other RNA processing events. In eukaryotic organisms and the viruses that infect them, RNA editing is frequently observed. Editing, like splicing, is a form of processing that modifies the information transfer process at the posttranscriptional level in order to increase genetic diversity and change the function of gene products. Editing, like splicing, has the potential to amplify genetic diversity.

ADAR1

ADAR1, which is encoded by the ADAR gene, ADAR2, which is encoded by ADARB1, and ADAR3, which is encoded by ADARB2, are the three members of the ADAR gene family that have been identified and studied for their RNA-editing functions at this time.

The messenger RNAs (mRNAs) of multiple proteins have been identified as direct targets of ADAR1, and they go through nonsynonymous amino-acid substitutions that have been linked to the development of cancer. Overexpression of ADAR1 results in the production of an oncogenic version of antizyme inhibitor 1 in hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), colorectal cancer (CRC), and breast cancer (BC) (AZIN1; S367G). Stabilised edited AZIN1 acts as an analogue of the enzyme ornithine decarboxylase (ODC) to prevent the antizyme-mediated degradation of ODC and cyclin D1. Accumulations of ODC and cyclin D1 lead to increased cell proliferation, as well as increased metastatic potential and the capacity to initiate tumours (17–21). ADAR1 is responsible for the promotion of tumorigenesis in cervical cancer (CC) by editing multiple sites within the YXXQ motif of bladder cancer-associated protein (BLCAP), which is normally a tumour suppressor. BLCAP that has been edited loses its ability to interact with signal transducer and activator of transcription 3 (STAT3), which leads to increased cell proliferation.

ADAR2 is the second A-to-I RNA editase that has been discovered, and it was initially 

Cloned in 1996. ADAR2 is also capable of editing itself. The function of ADAR2 as the primary RNA editase of the glutamate receptor subunit B (GluR-B) was initially uncovered. In a mouse model, the early onset of epilepsy is caused by underediting of the GluR-B (Q607R) gene. The functional significance of ADAR2-mediated editing of GluR-B was established through the observation that mice with mutated ADAR2 are prone to seizures and die early in the postnatal period. The translational impact of this connection was found in malignant human brain tumours in both adults and children, where ADAR2-mediated editing of GluR-B is reduced compared to control samples. These tumours were found in both adults and children. Although ADAR2-mutant mice do not have brain tumours, which is likely due to early postnatal death, these observations may explain the aggressive nature of these cancers and the neurologic symptoms that human patients experience.

Conclusion

Most companies will test RNA-editing on genetic diseases first. Adams says this is the best clinical test of the technology. A-to-G switches can be used to treat many diseases. More than 30 disease-linked genes are on Shape’s list of potential RNA-editing targets. Huss cites a common mutation in the kinase LRRK2 as an example.