John F. Atkins, Ph.D., D.Sc.
Research Professor

Contribution to Society

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.

Research Summary

Until recently it was assumed that once the translation reading frame is set at the initiation of protein synthesis, sequential non-overlapping triplet decoding does not permit a change in frame. Now we know that changes in frame occur at "special" sequences, and can involve more than a quarter of the ribosomes changing frame. In some cases this specific frameshifting is used to produce a set ratio of different functional proteins which share some sequence in common. An example is in the synthesis of the GagPol precursor of many retroviruses. In other cases, it is used as a sensor for autoregulatory purposes. An example is in the decoding of mammalian mRNAs whose product, antizyme, regulates cellular polyamine levels and which has recently been reported to target cyclin D1 for degradation. This frameshifting is highly conserved and the sequence of the 12 nucleotides around the shift site are identical in humans and the yeast, S. pombe. In collaboration with Ray Gesteland and Michael Howard in this department, we are investigating the mechanisms involved, the biological consequences of individual cases as well as the extent of occurrence.

The above category involves single nucleotide shifting, either backwards or forwards, to enter one or other of the alternative frames. However, ribosomes can also bypass blocks of nucleotides present in the mRNA being decoding. This is frame independent. We are investigating a case where half the ribosomes bypass a 50 nucleotide coding gap to fuse the information from two ORFs. Its study is revealing aspects of how reading frame is maintained in standard decoding.

The meaning of "stop" codons can be redefined.by context features so that they specify a specific standard amino acid. The purpose is to synthesize an elongated protein in addition to the standard product. The purpose of redefining one of the stop codons, UGA, in some instances is different. It is to specify the 21st encoded amino acid selenocysteine, which is highly reactive. We are studying both types of redefinition, which, like frameshifting, involves reprogrammed genetic decoding, or RECODING (a term coined by Ray Gesteland which is deservedly becoming widely accepted).

Recent Publications

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.

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.

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.

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.

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.

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.

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.

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.

.F. 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.

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.

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.

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.

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.

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.