A New Model for Nonsense-Mediated Decay
Errors in the replication and decoding of the genome can create products harmful to the cell. To protect against the effects of such errors, cells have quality control processes that survey, identify, and remove problematic molecules. The Arribere Lab studies how these quality control pathways work.
One quality control pathway is called Nonsense-Mediated mRNA Decay (NMD) and acts on mutations that create an early stop signal and shorten a protein. Mutations that introduce early stop signals are known to cause a substantial fraction (~11%) of human genetic diseases. During NMD, a cell identifies the early stop signal and then blocks further protein production. Despite much research, there is still no consensus on how cells identify early stop signals, nor how cells block further protein production.
We recently fortuitously trapped a novel intermediate of NMD. The intermediate occurs at early stop signals and is thought to be a complex of molecules including the ribosome, an mRNA, and a tRNA still bound to newly formed protein. The nature of the intermediate suggests several exciting hypotheses about the timing and events of NMD, and raises several puzzling questions. We will test these hypotheses and provide a clearer picture of how cells identify and repress genes with early stop signals. An understanding of NMD and stop signals will provide important fundamental insight into how genes are decoded, allow researchers to better anticipate the effects of new mutations, and may suggest new therapeutic approaches to treat diseases that arise as a result of NMD or early stop signals.
A substantial component of our research program involves experiments done in the roundworm C. elegans. C. elegans is a simple model organism that is extremely amenable to experimental manipulation. Importantly, C. elegans contains an NMD system very similar to that of humans. This allows us to use C. elegans as a training ground for NMD models, ideas, and experiments that we will later apply to understand human health and disease.