Positions

Overview

  • David Bedwell, Professor and Chairman of the Department of Biochemistry and Molecular Genetics, completed his undergraduate studies in Microbiology at Purdue University (B.S. with Honors, 1979). His graduate work in Molecular Biology was done with Dr. Masayasu Nomura at the University of Wisconsin-Madison, (Ph.D., 1985). He then carried out a postdoctoral fellowship in Dr. Scott Emr's laboratory at Caltech. Dr. Bedwell joined the faculty at UAB in 1988. At the national level, he is in a second 5 year term on the Editorial Board of the Journal of Biological Chemistry, and has served as chair of both the Molecular Genetics B (MGB) and Molecular Genetics C (MGC) Study Sections of the National Institutes of Health. He has reviewed manuscripts for >60 scientific journals (including Science, Nature, and Cell). He was elected Fellow of the American Academy of Microbiology in 2011. At the institutional level, he has served as chair of the UAB School of Medicine Faculty Council (2016) and also currently serves as the Co-Director of the UAB structural Biology Program. He previously served as Director the the UAB Cell and Molecular Biology (CMB) Graduate Program (1996-2002).
  • Selected Publications

    Academic Article

    Year Title Altmetric
    2017 Identification of the amino acids inserted during suppression of CFTR nonsense mutations and determination of their functional consequences.Human Molecular Genetics.  26:3116-3129. 2017
    2016 Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression.Proceedings of the National Academy of Sciences.  113:12508-12513. 2016
    2016 Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I.Disease Models & Mechanisms.  9:759-767. 2016
    2016 Discovery of Clinically Approved Agents That Promote Suppression of Cystic Fibrosis Transmembrane Conductance Regulator Nonsense Mutations.American Journal of Respiratory and Critical Care Medicine.  194:1092-1103. 2016
    2015 Both the autophagy and proteasomal pathways facilitate the Ubp3p-dependent depletion of a subset of translation and RNA turnover factors during nitrogen starvation in Saccharomyces cerevisiae.RNA.  21:898-910. 2015
    2014 Marked repression of CFTR mRNA in the transgenic Cftr(tm1kth) mouse model.Journal of Cystic Fibrosis.  13:351-352. 2014
    2014 Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor.American Journal of Respiratory Cell and Molecular Biology.  50:805-816. 2014
    2014 Long-term nonsense suppression therapy moderates MPS I-H disease progression.Molecular Genetics and Metabolism.  111:374-381. 2014
    2014 Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats.PLoS ONE.  9:e91253. 2014
    2014 Therapeutics based on stop codon readthrough.Annual Review of Genomics and Human Genetics.  15:371-394. 2014
    2013 Heterozygosity for the F508del mutation in the cystic fibrosis transmembrane conductance regulator anion channel attenuates influenza severity.Journal of Infectious Diseases.  208:780-789. 2013
    2013 Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression.PLoS ONE.  8:e60478. 2013
    2012 Suppression of premature termination codons as a therapeutic approach.Critical Reviews in Biochemistry and Molecular Biology.  47:444-463. 2012
    2012 Identification of eRF1 residues that play critical and complementary roles in stop codon recognition.RNA.  18:1210-1221. 2012
    2012 The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse.Molecular Genetics and Metabolism.  105:116-125. 2012
    2011 Suppression of CFTR premature termination codons and rescue of CFTR protein and function by the synthetic aminoglycoside NB54.The Clinical investigator.  89:1149-1161. 2011
    2011 Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases.Wiley Interdisciplinary Reviews: RNA.  2:837-852. 2011
    2011 Enhancement of alveolar epithelial sodium channel activity with decreased cystic fibrosis transmembrane conductance regulator expression in mouse lung.AJP - Lung Cellular and Molecular Physiology.  301:L557-L567. 2011
    2010 Corrigendum to "Characterization of an MPS I-H knock-in mouse that carries a nonsense mutation analogous to the human IDUA-W402X mutation" [Mol. Genet. Metab. 99 (2010) 62-71] (DOI:10.1016/j.ymgme.2009.08.002)Molecular Genetics and Metabolism.  99:439. 2010
    2010 Characterization of an MPS I-H knock-in mouse that carries a nonsense mutation analogous to the human IDUA-W402X mutation.Molecular Genetics and Metabolism.  99:62-71. 2010
    2009 Nonsense suppression activity of PTC124 (ataluren).Proceedings of the National Academy of Sciences.  106:E64. 2009
    2009 Connection between stop codon reassignment and frequent use of shifty stop frameshifting.RNA.  15:889-897. 2009
    2009 Poly-L-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a cystic fibrosis mouse model.Journal of Biological Chemistry.  284:6885-6892. 2009
    2008 Distinct eRF3 requirements suggest alternate eRF1 conformations mediate peptide release during eukaryotic translation termination.Molecular Cell.  30:599-609. 2008
    2008 PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model.Proceedings of the National Academy of Sciences.  105:2064-2069. 2008
    2008 Eukaryotic ribosomal RNA determinants of aminoglycoside resistance and their role in translational fidelity.RNA.  14:148-157. 2008
    2006 Eukaryotic release factor 1 phosphorylation by CK2 protein kinase is dynamic but has little effect on the efficiency of translation termination in Saccharomyces cerevisiae.Eukaryotic Cell.  5:1378-1387. 2006
    2006 Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model.The Clinical investigator.  84:573-582. 2006
    2006 Tpa1p is part of an mRNP complex that influences translation termination, mRNA deadenylation, and mRNA turnover in Saccharomyces cerevisiae.Molecular and Cellular Biology.  26:5237-5248. 2006
    2006 Aminoglycosides as potential pharmacogenetic agents in the treatment of Hailey-Hailey disease.Journal of Investigative Dermatology.  126:229-231. 2006
    2006 Distinct paths to stop codon reassignment by the variant-code organisms Tetrahymena and Euplotes.Molecular and Cellular Biology.  26:438-447. 2006
    2005 Pharmacological suppression of premature stop mutations that cause genetic diseasesCurrent Pharmacogenomics.  3:259-269. 2005
    2005 Inhibition of phosphoglucomutase activity by lithium alters cellular calcium homeostasis and signaling in Saccharomyces cerevisiae.American Journal of Physiology - Cell Physiology.  289:C58-C67. 2005
    2005 Discrimination between defects in elongation fidelity and termination efficiency provides mechanistic insights into translational readthrough.Journal of Molecular Biology.  348:801-815. 2005
    2004 The Ca2+ homeostasis defects in a pgm2Delta strain of Saccharomyces cerevisiae are caused by excessive vacuolar Ca2+ uptake mediated by the Ca2+-ATPase Pmc1p.Journal of Biological Chemistry.  279:38495-38502. 2004
    2004 GTP hydrolysis by eRF3 facilitates stop codon decoding during eukaryotic translation termination.Molecular and Cellular Biology.  24:7769-7778. 2004
    2004 Leaky termination at premature stop codons antagonizes nonsense-mediated mRNA decay in S. cerevisiae.RNA.  10:691-703. 2004
    2003 A Saccharomyces cerevisiae mutant unable to convert glucose to glucose-6-phosphate accumulates excessive glucose in the endoplasmic reticulum due to core oligosaccharide trimming.Eukaryotic Cell.  2:534-541. 2003
    2003 Extracellular Ca(2+) sensing contributes to excess Ca(2+) accumulation and vacuolar fragmentation in a pmr1Delta mutant of S. cerevisiae.Journal of Cell Science.  116:1637-1646. 2003
    2003 Extracellular Ca2+ sensing contributes to excess Ca2+ accumulation and vacuolar fragmentation in a pmr1Δ mutant of S. cerevisiaeJournal of Cell Science.  116:1637-1646. 2003
    2002 Intracellular glucose 1-phosphate and glucose 6-phosphate levels modulate Ca2+ homeostasis in Saccharomyces cerevisiae.Journal of Biological Chemistry.  277:45751-45758. 2002
    2002 Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene.The Clinical investigator.  80:595-604. 2002
    2002 Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system.The Clinical investigator.  80:367-376. 2002
    2002 Hexose phosphorylation and the putative calcium channel component Mid1p are required for the hexose-induced transient elevation of cytosolic calcium response in Saccharomyces cerevisiae.Microbiological sciences.  44:1299-1308. 2002
    2001 Overproduction of PDR3 suppresses mitochondrial import defects associated with a TOM70 null mutation by increasing the expression of TOM72 in Saccharomyces cerevisiae.Molecular and Cellular Biology.  21:7576-7586. 2001
    2001 Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis.American Journal of Respiratory and Critical Care Medicine.  163:1683-1692. 2001
    2001 Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation.Human Molecular Genetics.  10:291-299. 2001
    2000 Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system.RNA.  6:1044-1055. 2000
    2000 Loss of the major isoform of phosphoglucomutase results in altered calcium homeostasis in Saccharomyces cerevisiae.Journal of Biological Chemistry.  275:5431-5440. 2000
    1999 Mutations in the yeast Hsp40 chaperone protein Ydj1 cause defects in Axl1 biogenesis and pro-a-factor processing.Journal of Biological Chemistry.  274:34396-34402. 1999
    1999 The vacuolar Ca2+/H+ exchanger Vcx1p/Hum1p tightly controls cytosolic Ca2+ levels in S. cerevisiae.FEBS Letters.  451:132-136. 1999
    1999 The Golgi apparatus plays a significant role in the maintenance of Ca2+ homeostasis in the vps33Delta vacuolar biogenesis mutant of Saccharomyces cerevisiae.Journal of Biological Chemistry.  274:5939-5947. 1999
    1998 Cystic fibrosis transmembrane conductance regulator (CFTR) nucleotide-binding domain 1 (NBD-1) and CFTR truncated within NBD-1 target to the epithelial plasma membrane and increase anion permeability.Biochemistry.  37:15222-15230. 1998
    1998 sec mutants accelerate turnover of CFTR and δF508 CFTR-role for stress responsesFederation proceedings.  12. 1998
    1997 The amino terminus of the F1-ATPase beta-subunit precursor functions as an intramolecular chaperone to facilitate mitochondrial protein import.Molecular and Cellular Biology.  17:7169-7177. 1997
    1997 Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line.Nature Medicine.  3:1280-1284. 1997
    1996 Nonstop treatment of cystic fibrosis.Nature Medicine.  2:608-609. 1996
    1996 Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations.Nature Medicine.  2:467-469. 1996
    1996 Mutations within the first LSGGQ motif of Ste6p cause defects in a-factor transport and mating in Saccharomyces cerevisiae.Journal of Bacteriology.  178:1712-1719. 1996
    1995 The efficiency of translation termination is determined by a synergistic interplay between upstream and downstream sequences in Saccharomyces cerevisiae.Journal of Molecular Biology.  251:334-345. 1995
    1995 The posttranslational modification of phosphoglucomutase is regulated by galactose induction and glucose repression in Saccharomyces cerevisiae.Journal of Bacteriology.  177:3087-3094. 1995
    1994 The glycosylation of phosphoglucomutase is modulated by carbon source and heat shock in Saccharomyces cerevisiae.Journal of Biological Chemistry.  269:27143-27148. 1994
    1994 Premature translation termination mutations are efficiently suppressed in a highly conserved region of yeast Ste6p, a member of the ATP-binding cassette (ABC) transporter family.Journal of Biological Chemistry.  269:17802-17808. 1994
    1994 Characterization of the mitochondrial binding and import properties of purified yeast F1-ATPase beta subunit precursor. Import requires external ATP.Journal of Biological Chemistry.  269:7192-7200. 1994
    1993 A mitochondrial porin cDNA predicts the existence of multiple human porins.Journal of Biological Chemistry.  268:12143-12149. 1993
    1993 Phosphoglucomutase in Saccharomyces cerevisiae is a cytoplasmic glycoprotein and the acceptor for a Glc-phosphotransferase.Journal of Biological Chemistry.  268:8341-8349. 1993
    1992 Antibodies against the cystic fibrosis transmembrane regulator.American Journal of Physiology.  262:C396-C404. 1992
    1992 Antibodies against the cystic fibrosis transmembrane regulatorAmerican Journal of Physiology.  262. 1992
    1989 Sequence and structural requirements of a mitochondrial protein import signal defined by saturation cassette mutagenesis.Molecular and Cellular Biology.  9:1014-1025. 1989
    1987 The yeast F1-ATPase beta subunit precursor contains functionally redundant mitochondrial protein import information.Molecular and Cellular Biology.  7:4038-4047. 1987
    1987 Regulation of alpha operon gene expression in Escherichia coli. A novel form of translational coupling.Journal of Molecular Biology.  196:333-345. 1987
    1986 Feedback regulation of RNA polymerase subunit synthesis after the conditional overproduction of RNA polymerase in Escherichia coli.Molecular and General Genetics MGG.  204:17-23. 1986
    1985 Increased expression of ribosomal genes during inhibition of ribosome assembly in Escherichia coli.Journal of Molecular Biology.  184:23-30. 1985
    1985 Nucleotide sequence of the alpha ribosomal protein operon of Escherichia coli.Nucleic Acids Research.  13:3891-3903. 1985
    1983 The spc ribosomal protein operon of Escherichia coli: sequence and cotranscription of the ribosomal protein genes and a protein export gene.Nucleic Acids Research.  11:2599-2616. 1983
    1980 Characterization of a HindIII-generated DNA fragment carrying the glutamine synthetase gene of Salmonella typhimurium.Gene.  11:227-237. 1980

    Research Overview

  • The Bedwell lab seeks to understand the mechanistic details of translation termination in eukaryotes, and to use that knowledge to develop therapeutic strategies for a range of genetic diseases caused by premature translation termination mutations (PTCs). In addition, other important cellular processes also intersect with the process of translation termination. For example, conserved cellular machineries also regulate the abundance of mRNAs based on the location of stop codons through the process of Nonsense-Mediated mRNA Decay (NMD). We are using a combination of genetics, biochemistry, and cell biology to better understand the molecular details of these processes. Two diseases we are applying our findings to are cystic fibrosis (CF) and the lysosomal storage disease MPS I-H (Hurler syndrome). CF is caused by mutations in the CFTR gene. Roughly 10% of CF patients carry a premature stop mutation in the CFTR gene. We are working to identify drugs that suppress premature stop mutations in the CFTR gene in various experimental models, including cultured CF cells, transgenic and knock-in CF mice, and CF patients. We have also recently identified the amino acids inserted during the suppression of various stop codons in mammalian cells, and are using that informationto develop strategies to enhance the CFTR activity obtained by PTC suppression. Similarly, 70% of Mucopolysaccharidosis Type I-H (MPS I-H) patients carry a premature stop mutation in the IDUAgene. We have shown that PTC suppression can alleviate the primary biochemical defect in primary cells and a knock-in Hurler mouse. In addition, we have shown that this approach can also moderate long-term progression of this disease in the brain, bone and heart. Ultimately, this therapeutic approach could be usedto treat a broad range of human genetic diseases caused by premature stop mutations. Currently, our research is provided by the NIH, The University of Pennsylvania, and the Cystic Fibrosis Foundation.
  • Principal Investigator On

  • UAB CF Research and Translation Core Center - Core B  awarded by National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS 2018 - 2023
  • Exploring Nonsense Suppression as a Treatment for NF1  awarded by GILBERT GENE THERAPY INITIATIVE, LLC 2018 - 2021
  • The Identification of New Treatments for Cystic Fibrosis Caused by Premature Termination Codons-Bedwell Subcontract  awarded by SOUTHERN RESEARCH INSTITUTE 2015 - 2020
  • Identify Drugs to Treat MPS-IH Caused by Nonsense Mutations  awarded by University of Pennsylvania 2016 - 2019
  • UAB CF Research and Translation Core Center - Core B: Animal Models Core  awarded by National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS 2015 - 2018
  • New Nonsense Suppression Drugs to Treat MPS I  awarded by National Institute of Neurological Disorders and Stroke/NIH/DHHS 2014 - 2017
  • UAB CF Research and Translation Core Center - Core B  awarded by National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS 2012 - 2016
  • Tuning Aminoglycosides for Treatment of Genetic Diseases  awarded by Technion Israel Institute of Technology 2011 - 2015
  • Investigating Suppression Therapy to Treat MPS I-H  awarded by University of Pennsylvania 2011 - 2013
  • Suppression of the Idua-W402X Mutation in an MPS I-H Mouse  awarded by National Institute of Neurological Disorders and Stroke/NIH/DHHS 2007 - 2013
  • Mechanism of Eukaryotic Translation Termination  awarded by National Institute of General Medical Sciences/NIH/DHHS 2007 - 2012
  • UAB CF Research and Translation Core Center - Core B - Mouse Model Core  awarded by National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS 2007 - 2012
  • Assay of Aminoglycosides in a CF Mouse Model  awarded by Technion Israel Institute of Technology 2010 - 2011
  • Teaching Activities

  • GBSC720 - Journal Club 2 (Spring Term 2019) 2019
  • missing activity 2018
  • missing activity 2018
  • GBSC720 - Journal Club 2 (Fall Term 2017) 2017
  • GBSC720 - Journal Club 2 (Spring Term 2017) 2017
  • GBSC720 - Journal Club 2 (Fall Term 2016) 2016
  • missing activity 2016
  • missing activity 2015
  • MIC785 - Post-Trx Reg Mech Journal Club (Spring Term 2015) 2015
  • missing activity 2014
  • MIC785 - Post-Trx Reg Mech Journal Club (Spring Term 2014) 2014
  • missing activity 2013
  • missing activity 2013
  • missing activity 2012
  • GBS795 - Lab Rotation I (Summer Term 2012) 2012
  • missing activity 2012
  • missing activity 2012
  • GBS798 - Non dissertation Research (Summer Term 2012) 2012
  • missing activity 2012
  • missing activity 2012
  • missing activity 2012
  • GBS796 - Lab Rotation II (Spring Term 2012) 2012
  • missing activity 2011
  • missing activity 2011
  • GBS799 - Dissertation Research (Fall Term 2011) 2011
  • MIC785 - Post-Trx Reg Mech Journal Club (Fall Term 2011) 2011
  • missing activity 2011
  • missing activity 2011
  • missing activity 2011
  • missing activity 2011
  • GBS796 - Lab Rotation II (Spring Term 2011) 2011
  • GBS798 - Non dissertation Research (Spring Term 2011) 2011
  • GBS799 - Dissertation Research (Spring Term 2011) 2011
  • MIC785 - Post-Trx Reg Mech Journal Club (Spring Term 2011) 2011
  • missing activity 2010
  • missing activity 2010
  • missing activity 2010
  • GBS795 - Lab Rotation I (Fall Term 2010) 2010
  • missing activity 2010
  • MIC785 - Post-Transcription Reg Mech (Spring Term 2010) 2010
  • MIC785 - Post-Transcription Reg Mech (Fall Term 2009) 2009
  • 01-125 - CMB2 GENETICS (Fall Term 2009) 2009
  • missing activity 2009
  • missing activity 2008
  • CMB720 - CMB II Genes (Fall Term 2008) 2008
  • MIC785 - Post-Transcription Reg Mech (Fall Term 2008) 2008
  • missing activity 2008
  • MIC785 - Post-Transcription Reg Mech JC (Spring Term 2008) 2008
  • missing activity 2007
  • CMB720 - CMB II Genes (Fall Term 2007) 2007
  • missing activity 2007
  • Education And Training

  • Bachelor of Science or Mathematics in Microbiology, Purdue University System : Purdue University
  • Doctor of Philosophy in Molecular Biology, University of Wisconsin System : Madison
  • Full Name

  • David Bedwell
  • Blazerid

  • dbedwell