How stop codon pseudouridylation induces nonsense suppression

•Pseudouridine (Ψ) in the first position stabilizes the non-canonical base pairs in the second and third position through creating a major groove in the mRNA-tRNA helix.•Slight chemical imbalances in the cell results in higher stability for pseudouridylated codon-anticodon interaction for certain stop codons (Amber and Opal).•The pseudouridylated codon-anticodon structure is more stabilized compared to the normal non-cognate stop codon-tRNA anticodon interaction. This can explain the reason for nonsense suppression instead of termination of protein synthesis.•Nonsense suppression if controlled, can be a potential therapeutic for nonsense mutation where the sense codons are changed to stop codon through mutation that would result in immature protein translation and damage to the cell.