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Allan S Jacobson PhD

TitleProfessor and Chair Emeritus
Endowed TitleGerald L. Haidak, MD, and Zelda S. Haidak Professor in Cell Biology
InstitutionUMass Chan Medical School
DepartmentMicrobiology and Physiological Systems
AddressUMass Chan Medical School
55 Lake Avenue North
Worcester MA 01655
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentMicrobiology and Physiological Systems

    InstitutionT.H. Chan School of Medicine
    DepartmentNeuroNexus Institute

    InstitutionT.H. Chan School of Medicine
    DepartmentRNA Therapeutics Institute

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentImmunology and Microbiology Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program

    InstitutionUMass Chan Programs, Centers and Institutes
    DepartmentBioinformatics and Integrative Biology

    Collapse Biography 
    Collapse education and training
    Queens College, Flushing, NY, United StatesBABiology
    Brandeis University, Waltham, MA, United StatesPHDBiology

    Collapse Overview 
    Collapse Summary
    Focus: Cytoplasmic aspects of post-transcriptional regulation in eukaryotes
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    Academic Background

    Ph. D. (1971) Brandeis University

    Dr. Allan Jacobson, PhDTranslation termination, NMD, and the development of therapeutic nonsense suppression

    Unlike the other 61 triplets of the genetic code, the nonsense codons UAA, UAG, and UGA fail to encode amino acids and, instead, serve as translation termination signals. Nonsense codons generated by mutations, gene expression errors, or alternate splicing can inactivate gene function by promoting premature translational termination. The latter event leads to the production of only a truncated version of a protein and to mRNA destabilization by an mRNA quality control mechanism that we have dubbed nonsense-mediated mRNA decay (NMD). NMD is operative in essentially all eukaryotic cells examined and ensures that nonsense-containing mRNAs do not accumulate as substrates for the translation apparatus. In turn, the elimination of these transcripts prevents the accumulation of potentially toxic polypeptide fragments.

    Using the yeast Saccharomyces cerevisiaeas a model system, much of the work in my lab is targeted to understanding the mechanistic details of NMD. Our experiments have led us to formulate the faux UTR model for NMD in yeast (see below), and independent studies in higher organisms have provided strong support for the general applicability of this model to all eukaryotes. Our data indicate that premature and normal termination differ mechanistically, with premature termination being a relatively inefficient process that leads to the ribosomal recruitment of at least three key regulatory proteins (Upf1, Upf2/Nmd2, and Upf3). These factors subsequently function in the dissociation of the premature termination complex and in the recruitment of the decapping enzyme responsible for initiating decay of the transcript. With the goal of further testing the faux UTR model, current studies in the lab are attempting to: a) define the timing and interaction-dependencies of Upf1, Upf2/Nmd2, and Upf3 association with prematurely terminating ribosomes, b) delineate the protein:protein interactions that link the decapping enzyme to the UPF/NMD factors, c) evaluate the functional differences of normal vs. premature termination, and d) characterize the Upf1 activity that dissociates and/or remodels ribosomal subunits at premature termination codons. To address these goals, we exploit yeast genetics, RNA biology, cell-free translation, and, in collaboration with the Moore (UMMS) and Gelles (Brandeis) labs, single-molecule analyses of protein synthesis. Additional studies in the yeast system seek to characterize the physiological significance of endogenous NMD substrates, as well as the mechanism by which some transcripts harboring premature terminators (e.g., cytoplasmic YRA1 pre-mRNA) can escape NMD.

    In humans, nonsense mutations have been implicated in more than 2000 inherited diseases, including cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), hemophilias, lysosomal storage disorders, skin disorders, and various cancers. A substantial fraction of the genetic disorders that arise from nonsense mutations are disabling or fatal and have only palliative treatment options at best. Given the large number of individuals that are collectively afflicted by nonsense mutations, a therapeutic approach to nonsense suppression could be of considerable medical benefit. Of particular importance is the possibility that a drug capable of suppressing nonsense in a given gene would also be capable of having the same effect on nonsense mutations in a completely different gene. Thus, under ideal circumstances a single drug could have the potential to treat hundreds, if not thousands, of different disorders where the only commonality would be their common origin from nonsense alleles. With this objective in mind, Dr. Stuart Peltz and I co-founded PTC Therapeutics Inc. (http://ptcbio.com/) in 1998, an endeavor that led to the identification and characterization of ataluren (PTC124), a novel, orally bioavailable small molecule that selectively promotes readthrough of premature nonsense codons (Welch et al., 2007 - see publications). Ataluren is currently being evaluated in clinical trials for several different nonsense-mediated genetic disorders (see: http://ptcbio.com/).

    Figure 1The faux UTR model. In normal termination (a), the ribosome harboring a nascent polypeptide approaches the UAG termination codon (top), engages the UAG codon in the ribosomal aminoacyl (A) site, binds the release factors eRF1 (Sup45) and eRF3 (Sup35), and releases the completed polypeptide (middle). The ribosome subunits are released from the mRNA and made available for another round of translation on either the same mRNA or another mRNA (bottom). Normal termination is thought to be highly efficient, possibly because interactions between Pab1 (the poly(A)-binding protein) and ribosome-associated eRF3 (Sup35) enhance the ability of eRF3 to stimulate the activity of eRF1 (Sup45). The spatial relationships of Pab1 and the termination site are exaggerated, but are meant to indicate that the effect of Pab1 depends on its proximity to the termination event. In premature termination (b), a ribosome harboring a nascent polypeptide approaches a premature UAG termination codon (top); it engages the UAG codon in its A site, binds eRF1 (Sup45) and eRF3 (Sup35), and fails to release the incomplete polypeptide (middle). Subsequently, the NMD factors Upf1, Nmd2/Upf2 and Upf3 bind to the release factors, stimulating peptide hydrolysis and 60S ribosomal subunit dissociation (bottom). The association of the NMD factors with the ribosome is postulated to facilitate the recruitment of the Dcp1-Dcp2 decapping enzyme complex to the mRNA, by virtue of the interaction of Dcp2 with Upf1, and to promote mRNA decapping. Premature termination is thought to be inefficient because the termination site lacks proximal Pab1 and/or other factors that are associated with a normal 3'-UTR. From: Amrani et al. Nature Reviews Molecular Cell Biology 7: 415-415 (2006).

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    Rotation Projects

    Rotation projects generally address specific gene expression issues in yeast, including problems in NMD, general mRNA decay, and translation termination. Methodological approaches depend on time commitment, but could include yeast genetics, individual and genome-wide transcript analysis, in vitro translation, and protein:protein interaction studies.

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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. He F, Jacobson A. Nonsense-Mediated mRNA Decay: Degradation of Defective Transcripts Is Only Part of the Story. Annu Rev Genet. 2015; 49:339-66. PMID: 26436458.
      Citations: 156     Fields:    Translation:HumansAnimalsCells
    2. Jacobson A. Methods to our madness. RNA. 2015 Apr; 21(4):529-30. PMID: 25780125.
      Citations:    Fields:    
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