My long-term goal is an understanding of the molecular mechanisms that regulate mRNA stability in the yeast Saccharomyces cerevisiae. Recent work in my laboratory has been focused on nonsense mediated mRNA decay (NMD), the destabilization of an otherwise stable mRNA by a premature termination codon. We have defined the set of endogenous NMD substrates, demonstrated that they are available for NMD at every round of translation, and showed that premature termination and normal termination are not equivalent biochemical events. Our experiments demonstrate that premature termination is aberrant and that its NMD-stimulating defects are likely to be attributable to the ribosome's failure to terminate adjacent to a specific RNP structure or set of factors localized 3' to the stop codon. In the experiments of this proposal, we seek to follow up on these observations, test aspects of a new model, and, ultimately, arrive at a more definitive understanding of the link between translation termination and mRNA decay. In addition, we will also pursue two provocative observations, respectively indicating that the failure to complete the peptide hydrolysis step of termination may induce a specific endonucleolytic cleavage and that the 5' to 3' mRNA decay pathway might play only a minor role in yeast mRNA decay. To these ends, I plan to: a) define in detail the in vitro and in vivo events that distinguish premature (aberrant) termination from normal termination, b) elucidate the mechanistic connections between premature translation termination and the triggering of mRNA decay, c) identify the specific mRNAs associated with the critical NMD factors, Upflp and Nmd2p, d) characterize the putative endonucleolytic cleavage products of the can1-100 and his4-38 mRNAs, and e) compare the genome-wide expression profiles of total mRNA to those of poly(A)+ mRNA in wild-type cells and in cells defective in distinct steps of the 5' to 3' and 3' to 5' mRNA decay pathways.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Molecular Genetics C Study Section (MGC)
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Bender, Michael T
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University of Massachusetts Medical School Worcester
Schools of Medicine
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Jacobson, Allan (2017) The moment when translational control had a theory of everything. Nat Rev Mol Cell Biol 18:344
Roy, Bijoyita; Friesen, Westley J; Tomizawa, Yuki et al. (2016) Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc Natl Acad Sci U S A 113:12508-12513
Dong, Shuyun; Jacobson, Allan; He, Feng (2016) Correction: Degradation of YRA1 Pre-mRNA in the Cytoplasm Requires Translational Repression, Multiple Modular Intronic Elements, Edc3p, and Mex67p. PLoS Biol 14:e1002470
He, Feng; Jacobson, Allan (2015) Nonsense-Mediated mRNA Decay: Degradation of Defective Transcripts Is Only Part of the Story. Annu Rev Genet 49:339-66
Jacobson, Allan (2015) Methods to our madness. RNA 21:529-30
Celik, Alper; Kervestin, Stephanie; Jacobson, Allan (2015) NMD: At the crossroads between translation termination and ribosome recycling. Biochimie 114:2-9
Roy, Bijoyita; Leszyk, John D; Mangus, David A et al. (2015) Nonsense suppression by near-cognate tRNAs employs alternative base pairing at codon positions 1 and 3. Proc Natl Acad Sci U S A 112:3038-43
He, Feng; Jacobson, Allan (2015) Control of mRNA decapping by positive and negative regulatory elements in the Dcp2 C-terminal domain. RNA 21:1633-47
He, Feng; Li, Chunfang; Roy, Bijoyita et al. (2014) Yeast Edc3 targets RPS28B mRNA for decapping by binding to a 3' untranslated region decay-inducing regulatory element. Mol Cell Biol 34:1438-51
Tsanova, Borislava; Spatrick, Phyllis; Jacobson, Allan et al. (2014) The RNA exosome affects iron response and sensitivity to oxidative stress. RNA 20:1057-67

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