Our research is focused on cytoplasmic aspects of post-transcriptional regulation in eukaryotes. The lab’s early work addressed the function of the eukaryotic mRNA poly(A) tail and led to formulation of the closed-loop mRNP model for the regulation of mRNA translation and decay. We went on to consider the cis- and trans-acting determinants of mRNA stability and established a yeast system for the analysis of sequences and factors that regulate mRNA decay rates. These studies led us to identify and define the yeast NMD (nonsense-mediated mRNA decay) pathway and the Upf proteins central to its regulation.
Our studies of NMD led us to conclude that premature and normal translation termination differed mechanistically. Although the lab’s principal goal has been to elucidate fundamental pathways of gene expression, our understanding of possible differences in termination efficiency suggested that our knowledge of these pathways had great potential for clinical benefit. Accordingly, Dr. Jacobson co-founded PTC Therapeutics Inc. to develop readthrough drugs as a potential therapy for genetic disorders caused by nonsense mutations. The EU approval of the drug that was developed (ataluren/Translarna) as a first-in-class medicine for the treatment of Duchenne muscular dystrophy, and the large number of DMD patients currently being treated with the drug, are strong arguments that basic science can yield unanticipated medical benefits.
We continue to pursue a mechanistic understanding of NMD, a goal that depends on elucidating the differences between premature and normal translation termination, determining how premature termination is coupled to accelerated mRNA decay, and defining the roles and functional order for factors that activate and execute these processes.
