RNA events. No end to nonsense.

Abstract

Two of the hottest topics in eukaryotic gene expression research involve absolute nonsense: nonsense-mediated mRNA decay (NMD) and nonsense-associated altered splicing (NAS). “Nonsense” in this case refers to a type of mutation in mRNA transcripts that causes the protein synthesis machinery to terminate prematurely their translation into proteins. Nonsense mutations were originally thought to affect only the length, and therefore the function, of the encoded protein. However, it is now apparent that they can dramatically decrease the half-lives of mutant mRNAs as well as alter the pattern of precursor mRNA (pre-mRNA) splicing (see the figure). The molecular basis of the latter phenomenon (NAS) is particularly mysterious, because it is generally accepted that nonsense mutations cannot be recognized as nonsense until after the splicing process is complete. Two papers, one by Mendell et al. on page 419 of this issue (1) and another by Wilkinson and co-workers in a recent issue of Molecular Cell (2), now begin to unravel this mystery by showing that NMD and one type of NAS (reading frame-dependent NAS) are functionally distinct processes that rely on different, but overlapping, sets of proteins.