In the news

To investigate whether pseudouridylation (conversion of uridine into pseudouridine, a chemical isomer with different properties) in mRNA suppresses nonsense codons. Nonsense mutations disrupt gene coding sequences by producing a ‘stop’ or termination signal in the wrong place, resulting in a truncated protein with little or no function. They are associated with a range of serious genetic diseases, including cystic fibrosis, Duchenne muscular dystrophy, beta thalassaemia and haemophilia. 

The researchers made short artificial RNAs finishing with either a nonsense codon (UAA), a pseudouridylated nonsense codon (YAA) or a cytidine codon (CAA), to see what effect they had in vitro. They then used specific guide RNAs to induce pseudouridylation at a specific point in a reporter gene to look at the effect in vivo. 

Protein production from RNAs in vitro was essentially absent with the nonsense codon, but restored with the pseudouridylated nonsense codon to almost the same levels as for the normal cytidine codon. The in vivo assays showed low levels of pseudouridylation at the site of interest, and modest levels of suppression of the nonsense codon. The researchers also investigated which amino acids were specified by which pseudouridylated nonsense codons. 

Artificial guide RNAs can direct the pseudouridylation of mRNA nonsense codons at specific sites leading to nonsense suppression, with potential implications for the treatment of genetic diseases. More broadly, pseudouridylation of mRNA at many more sites (including normal codons) may change their decoding and represent a novel, naturally occurring form of RNA editing, effectively expanding the genetic code. 

This paper may herald the opening of another new chapter in the unfolding story of complexity that is the human genome. It was originally thought that deciphering the genetic coding sequences of the genome would reveal the ‘blueprint of life’, but new revelations about the role of different forms of RNA editing and of epigenetic coding have shown the marvellous but often baffling intricacy by which cells can apparently vary their genetic repertoire. This latest discovery is certainly an area for further exploration. 

As a potential therapeutic it has promise, but significant barriers exist; for example, the risk of affecting RNA editing in sites besides the target nonsense mutation.