The exceptions to standard decoding provide us with insights that contribute to our understanding of standard decoding but they are also important in their own right. Recoding is widely used by viruses, especially plant viruses, and current work is revealing the critical setting of this phenomenon in retroviruses and identifying new regulatory control points.
In decoding the information in some genes to yield their protein products, the standard readout rules are transitorily over-ridden – the phenomenon of recoding. In one type of recoding a proportion of the readout machinery changes reading register resulting in an extra product as well as that derived from standard decoding. Examples include proteins that are essential for HIV and the SARS causing viruses. Another example serves a sensor and effector of regulatory circuit that governs the level of polyamines. In humans their level is critical for the prevention of certain disease states including cancer and we have been studying analogs with a view to intervention. In yet another case an extensive region of coding sequence is translationally bypassed and its study is providing a novel portal for insights to the functioning of the readout machinery.
A different type of recoding is where the meaning of a coding unit is dynamically changed when it occurs at specific locations. We have found the contextual signals that cause a “stop” in a mammalian virus to instead allow the readout machinery to continue protein synthesis We are actively pursuing the type of “meaning redefinition” utilized by Foot and Mouth disease virus as it appears that its hosts do not use the same mechanism and it could be a target for small molecule intervention.
Though the readout machinery is dependent on proteins for it speed and accuracy, its central functions are mediated by RNA. More broadly, we are alert to the possibility that studies of the readout machinery may provide new clues as to how the process got started in the first place. Not only does RNA play a central role in the readout machinery, it is being found to play unexpectedly diverse roles in the functioning of human and other cells. These roles, and where appropriate their evolutionary implications, are the topic of a recent book co-edited with Ray Gesteland and Tom Cech.
References to Publications:
E. Gueguen, N.W. Wills, J.F. Atkins and E. Cascales. Transcriptional frameshifting rescues Citrobacter rodentium Type VI secretion by the production of two length variants from the prematurely interrupted tssM gene. PLOS Genet. In press.
H.J. Kwun, T. Toptan, S.R. da Silva, J.F. Atkins, P.S. Moore and Y. Chang. 2014. Human DNA Tumor viruses generate alternative reading frame proteins through repeat sequence recoding. Proc. Natl. Acad. Sci. USA 111, E4342-4349.
G. Loughran, M.-Y. Chou, I.P. Ivanov, I. Jungries, M. Kellis, A.M. Kiran, P.V. Baranov and J.F. Atkins. 2014. Evidence of efficient stop codon readthrough in four mammalian genes. Nucl. Acids Res. 42, 8928-8938.
E. Samatova, A.L. Konevega, N.M. Wills, J.F. Atkins and M.V. Rodnina. 2014. High-efficiency translational bypassing of 50 non-coding nucleotides specified by mRNA structure and nascent peptide. Nature Communications 5: 4459.
V. Sharma, M.-F. Prère, I. Canal, A.E. Firth, J.F. Atkins, P.V. Baranov and O. Fayet. 2014. Analysis of tetra- and hepta-nucleotide motifs promoting -1 ribosomal frameshifting in Escherichia coli. Nucl. Acids Res. 42, 7210-7225.
E. Goodenough, T.M. Robinson, M.B. Zook, K.M. Flanigan, J.F. Atkins, M.T. Howard and L.C. Eisenlohr. 2014. Cryptic MHC class1-binding peptides are revealed by aminoglycoside-induced stop codon readthrough into the 3’UTR. Proc. Natl. Acad. Sci. USA 111, 5670-5675.
S. Kurokawa, S. Eriksson, K.L. Rose, S. Wu, A.K. Motley, S. Hill, V.P. Winfrey, W.H. McDonald, M.R. Capecchi, J.F. Atkins, E.S.J. Arnér, K.E. Hill and R.F. Burk. 2014. Sepp1UF is a truncated N-terminal form of selenoprotein P that has peroxidase activity when coupled with thioredoxin reductase-1. Free Radical Biology & Medicine 69, 67-76.
J.F. Atkins and P.V. Baranov. 2013. Antibiotic re-frames decoding. Nature 503, 478-479.
P.B.F. O’Connor, G.-W. Li, J.S. Weissman, J.F. Atkins and P.V. Baranov. 2013. rRNA:mRNA pairing alters the length and the symmetry of mRNA protected fragments in ribosome profiling experiments. Bioinformatics 29, 1488-1491
I. Antonov, A. Coakley, J.F. Atkins, P.V. Baranov and M. Borodovsky. 2013. Identification of the nature of reading frame transitions observed in prokaryotic genomes. Nucl Acids Res. 41, 6514-6530.
G. Loughran, J.E. Libbey, S. Uddowla, M.F. Scallan, M.D. Ryan, R.S. Fujinami, E. Rieder and J.F. Atkins. 2013. Theiler’s murine encephalomyelitis and Foot-and Mouth Disease viruses in its functional utilization of the StopGo non-standard translation mechanism. J. Gen. Virol. 94, 348-353.
K.E. Hill, S. Wu, A.K. Motley, T.D. Stevenson, V.P. Winfrey, M.R. Capecchi, J.F. Atkins and R.F. Burk. 2012. Production of selenoprotein P (sepp1) by hepatocytes is central to selenium homeostasis. J. Biol. Chem. 287, 40414-40424.
Y. Fang, E.E. Treffers, Y. Li, A. Tas, Y. Li, Z. Sun, Y. van der Meer, A.H. de Ru, P.A. van Veelen, J.F. Atkins, E.J. Snijder and A.E. Firth. 2012. Efficient -2 frameshifting by mammalian ribosomes to synthesize a previously undiscovered arterivirus protein. Proc. Natl. Acad. Sci. USA 109, E2920-2928.
A.E. Firth, B.W. Jagger, H.M. Wise, C.C. Nelson, K. Parsawar, N.M. Wills, S. Napthine, J.K. Taubenberger, P. Digard and J.F. Atkins. 2012. Ribosomal frameshifting utilized in influenza A virus expression occurs within the sequence UCC_UUU_CGU and is in the +1 direction. Open Biol. 2: 120109.
B.W. Jagger, H.M. Wise, J.C. Kash, K.-A. Walters, N.M. Wills, Y.-l. Xiao, R. L. Dunfee, L.M. Schwartzman, A. Ozinsky, G.L. Bell, R.M. Dalton, A. Lo, S. Efstathiou, J.F. Atkins, A.E. Firth, J.K. Taubenberger and P. Digard. 2012.
An overlapping protein-coding region in Influenza A virus segment 3 modulates the host response. Science 337, 199-204 (article).
A.M. Michel, K.R. Choudhury, A.E. Firth, N.T. Ingolia, J.F. Atkins and P.V. Baranov. 2012. Observation of dually decoded regions of the human genome using ribosome profiling data. Genome Res. 22, 2219-2229.
G. Loughran, M.S. Sachs, J.F. Atkins and I.P. Ivanov. 2012. Stringency of start codon selection modulates autoregulation of translation initiation factor eIF5. Nucl. Acids Res. 40, 2898-906
Q. Ren, Q.S. Wang, A.E. Firth, M.M.Y. Chan, J.W. Gouw, M.M. Guarna, L.J. Foster, J.F. Atkins and E. Jan. 2012. Alternative reading frame selection mediated by a tRNA-like internal ribosome entry site. Proc. Natl. Acad. Sci. USA 109 E630-639.
J.F. Atkins, R.F. Gesteland and T.R. Cech (eds) 2010. RNA Worlds: From life’s origins to diversity in gene regulation. 361 pages. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
I.P. Ivanov, G. Loughran, M.S. Sachs and J.F. Atkins. 2010. Initiation context modulates autoregulation of eukaryotic translation initiation factor eIF1. Proc.Natl. Acad. Sci. USA in press.
J.F. Atkins and P.V. Baranov. 2010. The distinction between recoding and reassignment. Genetics 185, 1535-1536.
Y.-W. Chung, A.E. Firth and J.F. Atkins. 2010. Frameshifting in alphaviruses: a diversity of 3 stimulatory structures. J. Mol. Biol. 397, 448-456.
J.F. Atkins. 2010. Complementary studies in the histidine operon and on frameshifting: A compliment to what Roth has wrought. in The Lure of Bacterial Genetics: a Tribute to John Roth. S. Maloy, K. Hughes and J. Casadesus (eds.) pp. ASM Press. Washington DC.
I.P. Ivanov and J.F. Atkins. 2010. Recurrent Emergence of Catalytically Inactive Ornithine Decarboxylase Homologs Forms that likely have regulatory function. J. Mol. Evol. 70, 289-302.
I.P. Ivanov, J.F. Atkins and A.J. Michael. 2010. A profusion of upstream open reading frame mechanisms in polyamine-responsive translational regulation. Nucl. Acids Res. 38,
A.E. Firth and J.F. Atkins. 2010. Candidates in Astroviruses, Seadornaviruses, Cytorhabdoviruses and Coronaviruses for +1 frame overlapping genes accessed by leaky scanning. Virol. J. 7: 17.
A.E. Firth, B.J. Blitvich, N.M. Wills, C.L. Miller and J.F. Atkins. 2010. Evidence for ribosomal frameshifting and a novel overlapping gene in the genomes of insect-specific flaviviruses. Virol. 399, 153-166.
E.B. Melian, E. Hinzman, T. Nagasaki, A.E. Firth, N.M. Wills, A.S. Nouwens, B.J. Blitvich, J. Leung, A. Funk, J.F. Atkins. R. Hall and A.A. Khromykh. 2010. NS1’ of flaviviruses from the Japanese encephalitis subgroup is a product of ribosomal frameshifting and plays a role in viral neuro-invasiveness. J. Virol. 84, 1641-1647. Editor selected Spotlight feature in J. Virol. 84, 1213.
J.F. Atkins and R.F. Gesteland. 2010. eds. Recoding: Expansion of Decoding rules enriches gene expression. 466 pages. Springer, New York.
Bekaert, A.E. Firth, Y. Zhang, V. Gladyshev, J.F. Atkins and P.V. Baranov. 2010. Recode-2: new design, new search tools, and many more genes. Nucl. Acids Res. 38, D69-74 (Database issue).
A.E. Firth and J.F. Atkins. 2009. Evidence for a novel coding sequence overlapping the 5′-terminal ~90 codons of the Gill-associated and Yellow head Okavirus envelope glycoprotein gene. Virol J. 6:222.
A.E. Firth, E. Jan, Q.S. Wang and J.F. Atkins. 2009. Bioinformatic evidence for a stem-loop structure 5′-adjacent to the IGR-IRES and for an overlapping gene in the bee paralysis dicistroviruses. Virol. J. 6: 193.
N.T. Lao, A.P. Maloney, J.F. Atkins and T.A. Kavanagh. 2009. Versatile dual reporter gene systems for investigating stop codon readthrough in plants. PLoS One 4, e7354 (9 pages).
A.E. Firth and J.F. Atkins. 2009. A case for a CUG-initiated coding sequence overlapping torovirus ORF1a and encoding a novel 30kDa product. Virol. J. 6:136 (6 Pages).
A.E. Firth and J.F. Atkins. 2009. Analysis of the coding potential of the partially overlapping 3’ ORF in segment 5 of the plant fiji viruses. Virol. J. 6:32 (5 pages).
A.E. Firth and J.F. Atkins. 2009. A conserved predicted pseudoknot in the NS2A- encoding sequence of West Nile and Japanese encephalitis flaviviruses suggests NS1′ may derive from ribosomal frameshifting. Virol. J. 6:14 (6 Pages).
J.F. Atkins and G.R. Björk. 2009. A gripping tale of ribosomal frameshifting: Extragenic suppressors of frameshift mutations spotlight altered P-site realignment. Microbiol. Mol. Biol. Revs. 73, 178-210.
J.F. Atkins and R.F. Gesteland. 2008. Recoding. Getting more out of the message by shifting reading frame and redefining codon meaning. in Steitz, T. (ed.), The Mechanisms of Ribosome Function: Insights into protein synthesis, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/?t=BL0321840-Atkins). The series (www.hstalks.com)has been sold to pharmaceutical companies such as Novartis and J. & J. and to 60 Universities including Oxford and Harvard etc.)
N.M. Wills, M. O’Connor, C.C.Nelson, C.C. Rettberg, W. M. Huang, R.F. Gesteland and J.F. Atkins. 2008. Translational bypassing without peptidyl-tRNA anticodon scanning of coding gap mRNA. EMBO J. 27, 2533-2544.
I.P. Ivanov, G. Loughran and J.F. Atkins. 2008. Novel regulatory uORFs with unusual start codons. Proc. Natl. Acad. Sci. USA 105, 10079-10084. Featured in Editor’s choice Science 321 issue 5887. 18th July 2008
A.E. Firth. 2008. Bioinformatic analysis suggests that the Orbivirus VP6 cistron encodes an overlapping gene. Virol. J. 5: 48 (10 Pages) (publication from our lab)
A.E. Firth, B. Y.W. Chung, M.N. Fleeton, and J.F. Atkins. 2008. Discovery of frameshifting in Alphavirus 6K resolves a 20-year enigma. Virol. J. 5:108 (19 Pages)
A.E. Firth and J.F. Atkins. 2008. Bioinformatic analysis suggests that the Cypovirus 1 major core protein cistron harbours an overlapping gene. Virol. J. 5, 62 (4 pages).
A.E. Firth and J.F. Atkins. 2008. Bioinformatic analysis suggests that a conserved ORF in the waikaviruses encodes an overlapping gene. Arch. Virol. 153, 1379- 1383.
Y.-W. Chung, W.A. Miller, J.F. Atkins and A. E. Firth. 2008. An overlapping essential gene in the Potyviridae. Proc. Natl. Acad. Sci USA 105, 5897-5902.
Bekaert, I. P. Ivanov, J.F. Atkins and P. V. Baranov. 2008 OAF: Fast and reliable detection of sequences encoding antizymes in eukaryotic mRNAs. BMC Bioinformatics 9, 178 (10 Pages).
J.F. Atkins and M.D. Ryan. 2008. Foot and Mouth’s Achilles’ heel? Nature Biotech. 26, 1335-1336.
J.F. Atkins, N.M. Wills, G. Loughran, C.-Y. Wu, K. Parsawar, M.D. Ryan, C.H. Wang and C.C. Nelson. 2007. A case for “StopGo”: Reprogramming translation to augment codon meaning of GGN by specifying termination (Stop) in addition to glycine and continued translation (Go). RNA 13, 803-810.
J.F. Atkins and P.V. Baranov. 2007. Duality in the genetic code. Nature 448, 1004-1005.
I.P. Ivanov and J.F. Atkins. 2007. Ribosomal frameshifting in decoding antizyme mRNAs from yeast and protists to humans: close to 300 cases reveal remarkable diversity despite underlying conservation. Nucl. Acids Res. 35, 1842-1858.
I.P. Ivanov, A. Pittman, C.-B. Bin, R.F. Gesteland and J.F. Atkins. 2007. Novel antizyme gene in Danio rerio expressed in brain and retina. Gene 387, 87-92.
Matveeva, Y. Nechipurenko, L. Rossi, B. Moore, P. Sætrom, A.Y. Ogurtsov, J.F. Atkins and S.A Shabalina. 2007. Comparison of approaches for rational siRNA design leading to a new efficient and transparent method. Nucl. Acids Res. 35: e63. (10 pages).
K.E. Hill, J. Zhou, L.M. Austin, A.K. Motley, A.-J.L. Ham, G.E. Olson, J.F. Atkins, R.F. Gesteland, and R.F. Burk. 2007. The selenium-rich C-terminal domain of mouse selenoprotein P is necessary for supply of selenium to brain and testis but not for maintenance of whole-body selenium. J. Biol. Chem. 282, 10972-10980.
J.F. Atkins and R.F. Gesteland. 2006. Major update of article on “Frameshifting” in the Encyclopedia of Life Sciences. (John Wiley & Sons, Ltd)
P.V. Baranov, B. Vestergaard, T. Hamelryck, R. F. Gesteland, J. Nyborg and J. F. Atkins. 2006. Diverse bacterial genomes encode an operon of two genes, one of which is an unusual class-I release factor that potentially recognizes atypical mRNA signals other than normal stop codons. Biology Direct 1: 28.
Bekaert, J.F. Atkins and P.V. Baranov. 2006. ARFA: a program for automated annotation of bacterial release factors genes. Bioinformatics 22, 2463-2465.
V.W. Aoki, G.L. Christensen, J.F. Atkins, and D.T. Carrell. 2006. Identification of novel polymorphisms in the nuclear protein genes and their relationship with human sperm protamine deficiency and severe male infertility. Fertil. Steril. 86, 1416-1422.
G.L. Christensen, S.P. Wooding, I.P. Ivanov, J.F. Atkins and D.T. Carrell (2006) Sequencing and haplotype analysis of the activator of CREM in the testis ACT gene in populations of fertiles and infertile males. Mol. Hum.Reprod. 12, 257-262
L. Christensen, I. P. Ivanov, J. F. Atkins, B. Campbell, and D.T. Carrell. 2006. Identification of polymorphisms in the Hrb, GOPC, and Csnk2a2 genes in two men with globozoospermia. J. Andrology 27, 11-15.
G.L. Christensen, I.P. Ivanov, S. Wooding, J.F. Atkins, A. Mielnik, P.N. Schlegel and D.T. Carrell. 2006. Identification of polymorphisms and balancing selection in the male infertility candidate gene, Ornithine decarboxylase antizyme 3. BMC Med. Genet. 7, 27.
M. Petros, G. F. Graminski, S. Robinson, M.R. Burns, N. Kisiel, R. F. Gesteland, J. F. Atkins, D.L. Kramer, M.T. Howard and R.S. Weeks. 2006. Polyamine analogs with xylene rings induce antizyme frameshifting, deplete cellular polyamines, and inhibit cell growth. J. Biochem. (Tokyo)140, 657-666.
N.M. Wills and J.F. Atkins. 2006. The potential role of ribosomal frameshifting in generating of proteins implicated in neurodegenerative diseases. RNA in press.
M.B. Zook, M.T. Howard, S. Gomathinayagam, J.F. Atkins, and L.C. Eisenlohr. 2006. Epitopes derived from incidental ribosomal frameshifting gives rise to a protective CD 8+ response. J. Immunol. In press.
I.P. Ivanov, R.F. Gesteland and J.F. Atkins. 2006. Evolutionary specialization of Recoding: Frameshifting in the expression of S. cerevisiae antizyme mRNA is via an atypical antizyme shift site but is still +1. RNA 12, 332-337.
P.V. Baranov, O. Fayet, R.W. Hendrix and J.F. Atkins. 2006. Recoding in bacteriophages and bacterial IS elements. Trends in Genetics22, 174-181.
N.M. Wills, B. Moore, A. Hammer, R.F. Gesteland and J.F. Atkins. 2006. A functional -1 ribosomal frameshift signal in human paraneoplastic MA 3 gene. J. Biol. Chem. 281, 7082-7088.
Atkins, R.F. Gesteland, R.J. Jackson and N.M. Wills. 2006. The shapely mRNA: knotting ventured, knotting gained. in The RNA World , 3 rd Ed. R.F. Gesteland, T.R. Cech & J.F. Atkins, eds. pp. 437-467. Cold Spring Harbor Lab. Press. Cold Spring Harbor, New York.
R.F. Gesteland, T.R. Cech and J.F. Atkins. 2006. The RNA World. The Nature of modern RNA suggests a prebiotic RNA World. 768 pages. Cold Spring Harbor Lab. Press, Cold Spring Harbor, New York.
L.M. Petros, M.T. Howard, R.F. Gesteland, J.F. Atkins. 2005. Polyamine sensing during antizyme mRNA programmed frameshifting. Biochem. Biophys Res. Comm . 338 ,1478-1489.
M.T. Howard, G. Aggarwal, C. Anderson, S. Khatri, Flanigan, K. and J.F. Atkins. 2005. Recoding elements located adjacent to a subset of eukaryal selenocysteine-specifying UGA codons. EMBO J. 24, 1596-1607.
P.V. Baranov, A.W. Hammer, J. Zhou, R.F. Gesteland and J.F. Atkins. 2005. Transcriptional slippage in bacteria: distribution in sequenced genomes and utilization in IS element gene expression. GenomeBiology 6 , R25.
P.V. Baranov, C.M. Henderson, C.B. Anderson, R.F. Gesteland, J.F. Atkins and M.T. Howard. 2005. Programmed ribosomal frameshifting in decoding the SARS-CoV genome. Virology 332, 498-510.
D.J. Bucklin, N.M. Wills, R.F. Gesteland and J.F. Atkins. 2005. P-site pairing subtleties revealed by the effects of different tRNAs on programmed translational bypassing where anticodon re-pairing to mRNA is separated from dissociation. J. Mol. Biol. 345,39-49.
O.V. Matveeva, B.T. Folley, V.A. Nemtsov, R.F. Gesteland, S. Matsufuji, J.F. Atkins, A.Y. Ogurtsov, and S.A. Shabalina. 2004. Identification of regions in multiple sequence alignments thermodynamically suitable for targeting by consensus oligonucleotides: application to HIV genome. BMC Bioinformatics 5:44.
M.T. Howard, R.F. Gesteland and J.F. Atkins. 2004. Efficient stimulation of site-specific ribosome frameshifting by morpholino oligonucleotides. RNA 10 , 1653-1661.
Citation for the Zook et al 2006 that is already on the webpage is J Immunol 176, 928-6934.
Citation for the last Wills & Atkins publication already on the webpage is RNA 12, 1149-1153.
John Atkins, Ph.D.
Department of Human Genetics
University of Utah
15 N 2030 E Rm. 7410
Salt Lake City, Utah 84112-5330