The Meaning of NMD: Translate or Perish

Premature translation termination leads to a reduced mRNA level in all types of organisms. In eukaryotes, the phenomenon is known as nonsense-mediated mRNA decay (NMD). This is commonly regarded as the output of a specific surveillance and destruction mechanism that is activated by the presence of a premature translation termination codon (PTC) in an atypical sequence context. Despite two decades of research, it is still unclear how NMD discriminates between PTCs and normal stop codons. We suggest that cells do not possess any such mechanism and instead propose a new model in which this mRNA depletion is a consequence of the appearance of long tracts of mRNA that are unprotected by scanning ribosomes.

TrendsMutations that interrupt translation reduce mRNA levels in all organisms studied to date.It has long been thought that in eukaryotes this mRNA depletion is the function of a specific and evolutionarily conserved mRNA surveillance mechanism termed nonsense-mediated mRNA decay (NMD).On the contrary, we argue that NMD is a passive consequence of ribosomes being prematurely released from the mRNA.Low ribosome occupancy is the key determinant of NMD.