We don't realize the full extent of our genetic mutations. Nonsense-mediated mRNA degradation (NMD), or mRNA surveillance, is one of the pathways that masks the effect of DNA mutations. Certain DNA sequence mutations cause the corresponding mRNA to contain a premature stop signal, called a PTC. When mRNAs containing a PTC are translated into proteins, the protein is truncated, or shortened. Depending upon what portion of the protein is missing, truncated proteins may be nonfunctional or potentially dangerous. NMD surveys mRNAs for PTCs.
NMD is an evolutionarily conserved mechanism to eliminate imperfect mRNAs containing PTCs. Although NMD has been heavily investigated in lower eukaryotic organisms, researchers have only a vague outline of the process in mammals. As published in the September 1 issue of Genes & Development, Dr. Shigeo Ohno and colleagues have discovered an important parallel between worm NMD and human NMD.
C. elegans regulates NMD by the addition of phosphate groups to the proteins involved in the NMD pathway. Dr. Ohno and colleagues have cloned and characterized the human homolog of the C. elegans smg-1 gene, which they termed hSMG-1. Like its worm counterpart, hSMG-1 encodes a protein kinase, which phosphorylates a member of the NMD pathway. Dr. Ohno and colleagues demonstrated that inactivation of hSMG-1 inhibited NMD and thereby allowed for the translation and subsequent accumulation of truncated proteins.
Dr. Ohno is quick to point out, though, that the accumulation of truncated proteins is not necessarily a detrimental event - it may even be desirable. Dr. Ohno and colleagues are pursuing a therapeutic strategy involving the specific inactivation of NMD. It turns out that not all truncated proteins are nonfunctional or dangerous; some truncated proteins show normal, albeit limited, activity. Dr. Ohno and colleagues argue that, in some cases, the inhibition of NMD through hSMG-1 inactivation will allow for the accumulation of truncated proteins that can at least partially compensate for the genetic disorder. As one forth of all mutations in human genetic diseases and cancers are of the type that can target mRNA for NMD, this therapy could be of widespread application.