UMass Chan Medical School
Allan Jacobson, Ph.D., is the Gerald L. & Zelda S. Haidak Professor of Cell Biology at the UMass Chan Medical School in Worcester, Massachusetts. His research has been focused on three areas of post‐transcriptional control: mRNA stability regulation, translation termination mechanisms, and poly﴾A﴿ function. His early work defined a role for the poly﴾A﴿‐binding protein in translation initiation. This led him to formulate the closed‐loop model for messenger ribonucleoprotein ﴾mRNP﴿ 5’/3’ interactions that promote mRNA stability and translation, a foundation for understanding multiple aspects of cytoplasmic post‐transcriptional regulation in eukaryotes. He then established a yeast system to analyze the sequences and factors that regulate mRNA decay rates and, with it, discovered the nonsense‐mediated mRNA decay ﴾NMD﴿ pathway, its endogenous substrates, and the roles of the Upf proteins central to NMD regulation. Seeking to understand the translational basis for NMD, Jacobson demonstrated that premature and normal translation termination differed mechanistically, with premature termination being a significantly less efficient process. This breakthrough yielded a pioneering approach to treating genetic disorders when he co‐founded PTC Therapeutics Inc. to develop a translation termination readthrough drug as therapy for genetic disorders caused by nonsense mutations. The resulting drug ﴾ataluren/Translarna﴿ received EMA approval in 2014 as a first‐in‐class medicine for the treatment of nonsense‐mediated Duchenne muscular dystrophy. Recently, he showed that nonsense suppression is primarily attributable to mRNA:tRNA mispairing at codon positions 1 and 3, that NMD is a probabilistic quality control mechanism that detects errors occurring anytime during translation elongation, that machine learning provides reliable predictions of mRNA sequence contexts most likely to promote ribosomal readthrough of termination codons, and that individual decapping activators (including Upf1) bind distinct Dcp2 domains to activate the Dcp1/Dcp2 mRNA decapping enzyme and provide it with substrate specificity. He is a member of the American Academy of Microbiology and the American Academy of Arts & Sciences, and was co-recipient of the 2023 Gruber Prize in Genetics.
S07.4- Stop Codon Readthrough as a Therapeutic Approach to CF Attributable to Nonsense Mutations
Thursday, September 26, 2024
2:30 PM – 4:30 PM ET