Decoding the Language of mRNA Stability

Messenger RNA degradation plays a critical role in regulating transcript levels and is a major control point for modulating gene expression. A series of discoveries from our group have uncovered that a significant determinant for RNA degradation is the genetic code itself — a concept we call Codon Optimality.

We showed that mRNA decay rates are dictated by the percentage of codons deemed "optimal," based on the abundance of their cognate tRNAs relative to demand. Optimal codons are decoded rapidly by ribosomes, while non-optimal codons are read more slowly due to limiting tRNA concentration. The rate at which the ribosome decodes an mRNA ultimately determines transcript fate.

Most excitingly, the exact same mRNA sequence can differentially impact stability in distinct cell types — codon optimality is plastic and regulated from cell to cell. We leverage both yeast and mammalian systems to define the molecular interplay between the ribosome and the degradation complex.