Control of gene expression by translational recodingIntroductionProgrammed -1 Ribosomal FrameshiftingIntroduction and HistoryPRF in Viruses: The ``Golden Mean´´ and Possible Therapeutic ApplicationsComputational Identification of -1 PRF Signals: Genomic Frameshifting-1 PRF in Cellular mRNAs: mRNA Destabilization Elements and Regulation of Gene ExpressionProgrammed +1 Ribosomal FrameshiftingHistory of +1 PRF: Retrotransposable ElementsCellular +1 PRFOrnithine Decarboxylase AntizymeOther Examples of Cellular +1 FrameshiftingSelenocysteine and Pyrrolysine: The 21st and 22nd Amino AcidsSelenocysteinePyrrolysineTermination Codon ReadthroughHistory: In VirusesTermination Suppression in Cellular GenesTherapeutic ApplicationsSummaryAcknowledgmentsReferencesCONTROL OF GENE EXPRESSION BYTRANSLATIONAL RECODINGBy JONATHAN D. DINMANDepartment of Cell Biology and Molecular Genetics, University of Maryland,College Park, Maryland, USAI. Introduction . . . .................................................................... 130II. Programmed 1 Ribosomal Frameshifting ... .................................... 131A. Introduction and History...................................................... 131B. PRF in Viruses: The ‘‘Golden Mean’’ andPossible Therapeutic Applications . ........................................... 132C. Computational Identification of 1 PRF Signals:Genomic Frameshifting . . . .................................................... 133D. 1 PRF in Cellular mRNAs: mRNA Destabilization Elements andRegulation of Gene Expression ............................................... 135III. Programmed þ1 Ribosomal Frameshifting . . . .................................... 136A. History of þ1 PRF: Retrotransposable Elements ............................. 136B. Cellular þ1 PRF................................................................ 137IV. Selenocysteine and Pyrrolysine: The 21st and 22nd Amino Acids . .............. 139A. Selenocysteine . . . .............................................................. 139B. Pyrrolysine . . . .................................................................. 140V. Termination Codon Readthrough . ............................................... 141A. History: In Viruses ............................................................. 141B. Termination Suppression in Cellular Genes. . . . .............................. 141C. Therapeutic Applications. . .................................................... 142VI. Summary . .......................................................................... 142References. ......................................................................... 143AbstractLike all rules, even the genetic code has exceptions: these are genericallyclassified as ‘‘translational recoding.’’ Almost every conce ivable mode ofrecoding has been documented, including signals that redefine transla-tional reading frame and codon assignation. While first described inviruses, it is becomi ng clear that sequences that program elongatingribosomes to shift translational reading frame are widely used by organ-isms in all domains of life, thus expanding both the coding capacity ofgenomes and the modes through which gene expression can be regulatedat the posttranscriptional level. Instances of programmed ribosomalADVANCES IN PROTEIN CHEMISTRY AND 129 Copyright 2012, Elsevier Inc.STRUCTURAL BIOLOGY, Vol. 86 All rights reserved.DOI: 10.1016/B978-0-12-386497-0.00004-9frameshifting and stop codon reassignment are opening up new avenuesfor treatment of numerous inborn errors of metabol ism. The implicationsof these findings on human health are only beginning to emerge.I. IntroductionMany years ago, I took a Japanese colleague on a walking tour ofManhattan, starting in SoHo and ending up at Rockefeller Center. Havingcome from Tokyo, my guest was not so much overwhelmed by the crowdsas he was perplexed by the fact that New Yorkers tended to cross the streetagainst the light. By the time we had reached Times Square, he turned tome and said ‘‘I understand: don’t walk means run.’’ The point is thatsometimes rules can be safely and advantageously broken. Indeed, excep-tions to the rules provide the contrasting points of reference that enabledefinition of the rules themselves. Every hero needs a foil: there could beno Hamlet without Laertes.Consider the ‘‘Central Dogma’’ of molecular biology: information flowsfrom DNA to RNA to protein. The discovery of reverse transcriptaseshattered this rule and opened up broad new vistas in both our under-standing and ability to manipulate biological systems. Not insignificantly,this discovery garnered Nobel Prizes for Drs. Temin and Varmus, demon-strating that challenging the status quo can (sometimes) be very reward-ing. The genetic code is another set of rules defining how amino acids areencoded in nucleic acid sequences. Given that four nucleotide bases mustencode 20 amino acids, Nirenberg surmised that a minimum of threebases had to be used to encode one amino acid. Based on this and usingdefined templates in well-defined in vitro translation assay systems, hedeciphered the genetic code and demonstrated that it is the same inEscherichia coli, Xenopus laevis, and guinea pi g tissues: a universally con-served genetic code composed of nucleoside triplets. Given the organiza-tion of genetic information into triplet codons, it became apparent thatribosomes, the universally conserved protein synthetic machinery, have toaccurately recognize and decode bases three at a time in order to accu-rately translate the genetic information contained in mRNAs into proteins.These findings laid the foundation for investigatio ns designed to answerthe fundamental questions of translational accuracy and reading framemaintenance. As desc ribed elsewhere, the discoveries of exceptions to thegenetic code, generically termed translational ‘‘recoding,’’ have help ed to130 DINMANaddress these questions and have opened new vistas in our understandingof many other biological questions (reviewed in Atkins and Gesteland,2010). This chapter focuses on recent efforts to identify translationalrecoding signals in cellular genomes, and their known and hypotheticalroles as cis-acting elements in controlling gene expression.II. Programmed 1 Ribosomal FrameshiftingA. Introduction and HistoryProgrammed ribosomal frameshifting (PRF) is a translational recodingphenomenon historically associated with viruses and