2025
Engineering a genomically recoded organism with one stop codon
Grome M, Nguyen M, Moonan D, Mohler K, Gurara K, Wang S, Hemez C, Stenton B, Cao Y, Radford F, Kornaj M, Patel J, Prome M, Rogulina S, Sozanski D, Tordoff J, Rinehart J, Isaacs F. Engineering a genomically recoded organism with one stop codon. Nature 2025, 639: 512-521. PMID: 39910296, PMCID: PMC11903333, DOI: 10.1038/s41586-024-08501-x.Peer-Reviewed Original Research
2023
Mistranslation of the genetic code by a new family of bacterial transfer RNAs
Schuntermann D, Fischer J, Bile J, Gaier S, Shelley B, Awawdeh A, Jahn M, Hoffman K, Westhof E, Söll D, Clarke C, Vargas-Rodriguez O. Mistranslation of the genetic code by a new family of bacterial transfer RNAs. Journal Of Biological Chemistry 2023, 299: 104852. PMID: 37224963, PMCID: PMC10404621, DOI: 10.1016/j.jbc.2023.104852.Peer-Reviewed Original ResearchConceptsTransfer RNAsAmino acidsBacterial transfer RNAsUnfavorable environmental conditionsProlyl-tRNA synthetaseWrong amino acidPoor substrate specificitySubstrate discriminationGrowth defectTransfer RNAGenetic codePosttranslational modificationsProtein reporterTranslation factorsEnvironmental stressFunctional proteinsSubstrate specificityThreonine codonGenetic informationDistinct isoformsPro mutationAntibiotic carbenicillinEscherichia coliNovel familyEnvironmental conditions
2022
Ancestral archaea expanded the genetic code with pyrrolysine
Guo LT, Amikura K, Jiang HK, Mukai T, Fu X, Wang YS, O’Donoghue P, Söll D, Tharp JM. Ancestral archaea expanded the genetic code with pyrrolysine. Journal Of Biological Chemistry 2022, 298: 102521. PMID: 36152750, PMCID: PMC9630628, DOI: 10.1016/j.jbc.2022.102521.Peer-Reviewed Original ResearchConceptsAminoacylation efficiencyGenetic code expansionDomains of lifePyrrolysyl-tRNA synthetaseTRNA-binding domainFull-length enzymeNoncanonical amino acidsAmino acid substratesMolecular phylogenyDiverse archaeaCoevolutionary historyTRNA sequencesGenetic codeCode expansionDiscriminator basesMethanogenic archaeaMethanosarcina mazeiPylRSSubstrate spectrumTRNAArchaeaMultiple organismsLiving cellsAcid substratesAmino acidsDiversification of aminoacyl-tRNA synthetase activities via genomic duplication
Krahn N, Söll D, Vargas-Rodriguez O. Diversification of aminoacyl-tRNA synthetase activities via genomic duplication. Frontiers In Physiology 2022, 13: 983245. PMID: 36060688, PMCID: PMC9437257, DOI: 10.3389/fphys.2022.983245.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsGenomic duplicationSynthetase familyRecent bioinformatic analysisAminoacyl-tRNA synthetase familySynthetic biology applicationsDomains of lifeNew drug targetsAminoacyl-tRNA synthetase activityGene duplicationPhylogenetic diversityEvolutionary eventsGenetic codeBioinformatics analysisImportant bioactive moleculesAdaptive advantageBiological functionsBiological processesBiology applicationsDrug targetsDuplicationAaRSsCatalytic siteSynthetase activityProteinBioactive moleculesThe tRNA discriminator base defines the mutual orthogonality of two distinct pyrrolysyl-tRNA synthetase/tRNAPyl pairs in the same organism
Zhang H, Gong X, Zhao Q, Mukai T, Vargas-Rodriguez O, Zhang H, Zhang Y, Wassel P, Amikura K, Maupin-Furlow J, Ren Y, Xu X, Wolf YI, Makarova KS, Koonin EV, Shen Y, Söll D, Fu X. The tRNA discriminator base defines the mutual orthogonality of two distinct pyrrolysyl-tRNA synthetase/tRNAPyl pairs in the same organism. Nucleic Acids Research 2022, 50: gkac271-. PMID: 35466371, PMCID: PMC9071458, DOI: 10.1093/nar/gkac271.Peer-Reviewed Original ResearchConceptsGenetic code expansionCode expansionDistinct non-canonical amino acidsOrthogonal aminoacyl-tRNA synthetase/tRNA pairsAminoacyl-tRNA synthetase/tRNA pairsPyrrolysyl-tRNA synthetase/Halophilic archaeon Haloferax volcaniiAdditional coding capacityDistinct noncanonical amino acidsNon-canonical amino acidsArchaeon Haloferax volcaniiDiscriminator baseAmino acidsPyrrolysyl-tRNA synthetaseNoncanonical amino acidsSite-specific incorporationMotif 2 loopSingle base changeDistinct tRNAsTRNA pairsHaloferax volcaniiUAA codonGenetic codeDiscriminator basesTRNA structureMeasuring the tolerance of the genetic code to altered codon size
DeBenedictis EA, Söll D, Esvelt KM. Measuring the tolerance of the genetic code to altered codon size. ELife 2022, 11: e76941. PMID: 35293861, PMCID: PMC9094753, DOI: 10.7554/elife.76941.Peer-Reviewed Original ResearchConceptsFour-base codonsGenetic codeTRNA mutationsAminoacyl-tRNA synthetasesQuadruplet codonsSingle amino acidCodon translationTriplet codonsTRNA synthetasesSynthetic biologistsCodonTRNAAmino acidsChemical alphabetsMutationsMass spectrometrySynthetasesAnticodonToleranceSynthetic systemsBiologistsTranslationEscherichiaNascentKhorana, Har Gobind
Söll D, RajBhandary U. Khorana, Har Gobind. 2022 DOI: 10.1016/b978-0-12-822563-9.00089-5.Peer-Reviewed Original ResearchGene synthesisDNA genesChemical synthesisChemical biologyGenetic codeMembrane proteinsDNA mutagenesisDNA sequencesSynthesis of DNABacterio-opsinG proteinsSuch profound effectsProton pumpMRNA synthesisGenesDNA sequencingBiological researchSynthesisBiologyPCR amplificationDNA chipChemistryNucleic acidsDNA diagnosticsProtein
2021
Genomics of Obsessive-Compulsive Disorder—Toward Personalized Medicine in the Era of Big Data
Szejko N, Dunalska A, Lombroso A, McGuire JF, Piacentini J. Genomics of Obsessive-Compulsive Disorder—Toward Personalized Medicine in the Era of Big Data. Frontiers In Pediatrics 2021, 9: 685660. PMID: 34746045, PMCID: PMC8564378, DOI: 10.3389/fped.2021.685660.Peer-Reviewed Original ResearchPsychiatric Genomics ConsortiumCommon disease-common variant hypothesisCommon variant hypothesisContext of genomicsGenetic codeGenetic association studiesMultiple genesAssociation studiesGenomics ConsortiumPolygenic risk scoresGenomicsGenetic contributionMendelian randomizationPolygenic disorderPersonalized medicineObsessive-compulsive disorderUK BiobankNew pathwayOCD pathogenesisAvailable databasesGenesDisease-specific databasesChina Kadoorie BiobankPathwayCo-existing pathologyPhosphorylated WNK kinase networks in recoded bacteria recapitulate physiological function
Schiapparelli P, Pirman NL, Mohler K, Miranda-Herrera PA, Zarco N, Kilic O, Miller C, Shah SR, Rogulina S, Hungerford W, Abriola L, Hoyer D, Turk BE, Guerrero-Cázares H, Isaacs FJ, Quiñones-Hinojosa A, Levchenko A, Rinehart J. Phosphorylated WNK kinase networks in recoded bacteria recapitulate physiological function. Cell Reports 2021, 36: 109416. PMID: 34289367, PMCID: PMC8379681, DOI: 10.1016/j.celrep.2021.109416.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCell Line, TumorCell MovementCell ProliferationEscherichia coliFemaleGlioblastomaHEK293 CellsHumansMaleMice, NudeMiddle AgedPhosphorylationPhosphoserineProtein Serine-Threonine KinasesRecombinant ProteinsSignal TransductionSmall Molecule LibrariesSubstrate SpecificityWNK Lysine-Deficient Protein Kinase 1ConceptsKinase networkAuthentic post-translational modificationsGenetic code expansionPost-translational modificationsProduction of proteinsSmall molecule kinase inhibitorsKinase inhibitorsGenetic codePhosphorylated proteinsCode expansionKinase proteinWNK kinasesPhysiological functionsWNK4 kinaseBiochemical propertiesGlioblastoma cellsKinaseBacterial strainsProteinDistinct sitesPhosphoserineSPAKBacteriaCellular systemsCells
2018
Debugging the genetic code: non-viral in vivo delivery of therapeutic genome editing technologies
Piotrowski-Daspit AS, Glazer P, Saltzman WM. Debugging the genetic code: non-viral in vivo delivery of therapeutic genome editing technologies. Current Opinion In Biomedical Engineering 2018, 7: 24-32. PMID: 30984891, PMCID: PMC6456264, DOI: 10.1016/j.cobme.2018.08.002.Peer-Reviewed Original ResearchGenome editingNon-viral delivery methodsCRISPR/Cas9 systemGenome engineering technologiesGenome editing technologyTherapeutic genome editingPeptide nucleic acidSpecific cell typesGenetic codeVivo deliveryCas9 systemEditing technologyEfficient deliveryGenomic mutationsCell typesPolymeric vehiclesFuture outlookDisease phenotypePrecise technologyEngineering technologyDelivery methodsNucleic acidsCell culturesEditingHereditary disease
2016
Codon identity regulates mRNA stability and translation efficiency during the maternal‐to‐zygotic transition
Bazzini AA, del Viso F, Moreno‐Mateos M, Johnstone TG, Vejnar CE, Qin Y, Yao J, Khokha MK, Giraldez AJ. Codon identity regulates mRNA stability and translation efficiency during the maternal‐to‐zygotic transition. The EMBO Journal 2016, 35: 2087-2103. PMID: 27436874, PMCID: PMC5048347, DOI: 10.15252/embj.201694699.Peer-Reviewed Original ResearchConceptsZygotic transitionMRNA stabilityTranslation efficiencyMRNA clearanceMaternal mRNAsCodon identityCodon compositionGene expressionMaternal mRNA clearanceRegulated mRNA decayPost-transcriptional mechanismsAmino acid sequenceTranscript decayMRNA decayPolyadenylation statusAmino acid compositionCodon tripletsGenetic codeSynonymous codonsAcid sequenceCellular transitionsRegulatory informationNew transcriptionDevelopmental progressionMRNA
2015
Overcoming Challenges in Engineering the Genetic Code
Lajoie M, Söll D, Church G. Overcoming Challenges in Engineering the Genetic Code. Journal Of Molecular Biology 2015, 428: 1004-1021. PMID: 26348789, PMCID: PMC4779434, DOI: 10.1016/j.jmb.2015.09.003.Peer-Reviewed Original ResearchInside Cover: Chemical Evolution of a Bacterial Proteome (Angew. Chem. Int. Ed. 34/2015)
Hoesl M, Oehm S, Durkin P, Darmon E, Peil L, Aerni H, Rappsilber J, Rinehart J, Leach D, Söll D, Budisa N. Inside Cover: Chemical Evolution of a Bacterial Proteome (Angew. Chem. Int. Ed. 34/2015). Angewandte Chemie International Edition 2015, 54: 9726-9726. DOI: 10.1002/anie.201506522.Peer-Reviewed Original Research
2014
Revealing the amino acid composition of proteins within an expanded genetic code
Aerni HR, Shifman MA, Rogulina S, O'Donoghue P, Rinehart J. Revealing the amino acid composition of proteins within an expanded genetic code. Nucleic Acids Research 2014, 43: e8-e8. PMID: 25378305, PMCID: PMC4333366, DOI: 10.1093/nar/gku1087.Peer-Reviewed Original ResearchConceptsNon-standard amino acidsOrthogonal translation systemGenetic codeUAG codonProtein synthesisConventional proteomic analysisRecombinant reporter proteinRelease factor 1Amino acid insertionAmino acid compositionReporter proteinProteomic analysisExtended proteinSurprising diversityUAG readthroughAcid insertionProteomic workflowStop codonNative proteinCodonEscherichia coliAmino acidsMessenger RNAUAGProteinExpanded Cellular Amino Acid Pools Containing Phosphoserine, Phosphothreonine, and Phosphotyrosine
Steinfeld JB, Aerni HR, Rogulina S, Liu Y, Rinehart J. Expanded Cellular Amino Acid Pools Containing Phosphoserine, Phosphothreonine, and Phosphotyrosine. ACS Chemical Biology 2014, 9: 1104-1112. PMID: 24646179, PMCID: PMC4027946, DOI: 10.1021/cb5000532.Peer-Reviewed Original ResearchConceptsNonstandard amino acidsAmino acidsGenetic codeOrthogonal aminoacyl-tRNA synthetaseCellular amino acid poolsIntracellular levelsPhosphorylated amino acidsAminoacyl-tRNA synthetaseE. coliLow-phosphate mediumAmino acid poolCotranslational insertionTRNA pairsMetabolic engineeringRecombinant proteinsDeficient cellsStandard amino acidsProtein synthesisWT cellsPhosphoserinePhosphotyrosinePhosphothreonineProteinAcid poolColi
2013
Genomically Recoded Organisms Expand Biological Functions
Lajoie MJ, Rovner AJ, Goodman DB, Aerni HR, Haimovich AD, Kuznetsov G, Mercer JA, Wang HH, Carr PA, Mosberg JA, Rohland N, Schultz PG, Jacobson JM, Rinehart J, Church GM, Isaacs FJ. Genomically Recoded Organisms Expand Biological Functions. Science 2013, 342: 357-360. PMID: 24136966, PMCID: PMC4924538, DOI: 10.1126/science.1241459.Peer-Reviewed Original ResearchConceptsNew genetic codesRelease factor 1UAG stop codonNonstandard amino acidsEscherichia coli MG1655UAA codonGenetic codeColi MG1655Biological functionsStop codonChemical diversityT7 bacteriophageAmino acidsFactor 1CodonMG1655OrganismsProteinDiversityDeletionBacteriophagesViral resistanceTranslation functionGROVivoUGA is an additional glycine codon in uncultured SR1 bacteria from the human microbiota
Campbell JH, O’Donoghue P, Campbell AG, Schwientek P, Sczyrba A, Woyke T, Söll D, Podar M. UGA is an additional glycine codon in uncultured SR1 bacteria from the human microbiota. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 5540-5545. PMID: 23509275, PMCID: PMC3619370, DOI: 10.1073/pnas.1303090110.Peer-Reviewed Original ResearchConceptsFrame TGA codonTGA codonGlycine codonHuman microbiotaSingle-cell genome sequencesSmall subunit rRNA sequencesComparative genomic analysisHorizontal gene transferUnique genetic codeGlycyl-tRNA synthetaseHuman Microbiome Project dataStrain-specific variationMost genesSuch taxaBisphosphate carboxylaseGenome sequenceGenetic codeGenomic analysisStriking diversityRRNA sequencesΒ-galactosidase activityGlycine residueStop codonCodonLacZ geneChlamydial Diseases
Johnson R. Chlamydial Diseases. 2013, 469-497. DOI: 10.1007/978-3-642-30144-5_111.ChaptersHost speciesSpecific host speciesTissue tropismBacterial adaptationGenetic codeEnvironmental nichesSpecific nichesAdaptive host defensesHuman diseasesChlamydia speciesSpeciesPathogenic bacteriaChlamydia researchChlamydiaeAbsolute dependenceHost defenseNicheChlamydial diseaseBacteriaHostDefenseTropismHuman illnessPathogensVaccine development
2012
The genetic code: Yesterday, today, and tomorrow
Ling J, Söll D. The genetic code: Yesterday, today, and tomorrow. Resonance 2012, 17: 1136-1142. DOI: 10.1007/s12045-012-0130-8.Peer-Reviewed Original ResearchGenetic codePhysiologyYeast mitochondrial threonyl-tRNA synthetase recognizes tRNA isoacceptors by distinct mechanisms and promotes CUN codon reassignment
Ling J, Peterson KM, Simonović I, Cho C, Söll D, Simonović M. Yeast mitochondrial threonyl-tRNA synthetase recognizes tRNA isoacceptors by distinct mechanisms and promotes CUN codon reassignment. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 3281-3286. PMID: 22343532, PMCID: PMC3295322, DOI: 10.1073/pnas.1200109109.Peer-Reviewed Original ResearchMeSH KeywordsAeropyrumAmino Acid SequenceAnticodonCatalytic DomainCodonCrystallography, X-RayEscherichia coliEvolution, MolecularLeucineMitochondriaModels, MolecularMolecular Sequence DataProtein ConformationProtein Structure, TertiaryRNA EditingRNA, Transfer, Amino AcylSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSequence AlignmentSpecies SpecificityStaphylococcus aureusSubstrate SpecificityThreonineThreonine-tRNA LigaseConceptsThreonyl-tRNA synthetaseAnticodon loopAnticodon sequenceEscherichia coli ThrRSSet of tRNAsDistinct recognition mechanismsAnticodon-binding domainAminoacyl-tRNA synthetasesCUN codonsDetailed structural comparisonCodon reassignmentYeast mitochondriaGenetic codeTRNA isoacceptorsSaccharomyces cerevisiaeIsoacceptor tRNAsEditing domainTRNAMST1Anticodon tripletStructural comparisonNatural tRNAAmino acidsDistinct mechanismsRecognition mechanism
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