Research in my lab focuses on RNA decay pathways. One pathway, called nonsense-mediated mRNA decay (NMD) or mRNA surveillance, surveys all newly synthesized mRNAs during what we call a "pioneer" round of translation. This round of translation involves mRNA that is associated with the cap binding heterodimer CBP80 and CBP20. It is distinct from the type of translation that supports the bulk of cellular protein synthesis and involves a different cap binding protein, eukaryotic initiation factor (eIF) 4E. Generally, if translation terminates more than 50-55 nt upstream of an exon-exon junction that is marked by the NMD factors Upf3 or Upf3X, Upf2 and ultimately Upf1, then the mRNA will be subject to NMD. By the time CBP80 and CBP20 have been replaced by eIF4E, the Upf mark has been removed so that mRNA is immune to NMD.
Studies in progress will significantly advance our understanding of the mRNP proteins, translation factors and nucleases that trigger NMD. Our results will be useful when designing therapies that aim to abrogate NMD in order to abrogate the severity of nonsense-generated diseases. We are also interested in further characterizing the pioneer translation initiation complex and requirements for its remodeling to the steady-state initiation complex that involves eIF4E. Additionally, we are interested in the cycle of posttranslational modifications that typify at least some of the NMD factors, including phosphorylation of Upf1 that is mediated by the PI 3-kinase-related protein kinase Smg1.
We have also uncovered a new mRNA decay pathway that we call Staufen (Stau)1-mediated mRNA decay (SMD). This pathway provides cells with a previously unappreciated means to regulate gene expression posttranscriptionally. We have found that the double-stranded RNA binding protein Stau1 recruits the NMD factor Upf1 to mRNAs, a number of which have been identified using microarray analysis in collaboration with Luc DesGroseillers (Université de Montréal). For those mRNAs that we have studied in detail, Stau1 recruits Upf1 to the 3' UTR and elicits mRNA decay in way that depends on translation termination at the normal (i.e., upstream) termination codon. By so doing, Stau1 bypasses the need for the Upf3 or Upf3X and Upf2 NMD factors, which serve to recruit Upf1 during NMD. More recent microarray and other types of analyses of mRNAs that are upregulated when Stau1 is downregulated indicate that SMD is widely used by cells as a means of posttranscriptional control.
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