Suppression and degradation of UpA dinucleotide-containing messenger RNAs and the impact of nucleotide modifications on stability

Abstract

Messenger RNA (mRNA) is strictly regulated in cells. Ever since its discovery, science has been trying to create drugs from mRNA, which finally materialized in the form of the recent severe acute respiratory syndrome coronavirus 2 messenger RNA vaccines. Stability has long been an issue in mRNA vaccine design. The instability of mRNA molecules can partly be found in the composition and modification of its nucleotides. Pseudouridine nucleotide modifications stabilized mRNA enough for clinical use, whereas RNAs high in adenosine and uridine nucleotides or those containing UpA or CpG dinucleotides are degraded more quickly than RNAs lacking the (di)nucleotides. This leads to a natural suppression of CpG and UpA dinucleotides in mRNA. The cause of CpG dinucleotide suppression can be found in DNA methylation, where methylated CpG DNA can spontaneously deaminate into TpG dinucleotides. The cause of UpA dinucleotide suppression is however unconfirmed but might find its roots in RNA editing, CpG methylation or gene expression. Degradation of UpA dinucleotide-containing mRNAs is similarly uncertain and may be attributed to RNase L or AU-rich element RNA binding proteins (AUBP), which can stabilize or destabilize mRNA. Herein, current theories on UpA suppression and degradation will be reviewed in addition to adenosine and uridine modifications to discuss which factors surrounding (di)nucleotides and nucleotide modifications influence the stability of mRNA. Finally, this review hypothesizes a link between evolution towards UpA dinucleotide suppression and avoidance of destabilizing AUBP binding.