John F. Atkins
Research Professor of Human Genetics
B.A. Dublin University
Ph.D. Dublin University
Sc.D. Dublin University
Research
Until recently it was assumed that once the reading frame is set at translation initiation, sequential 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 third of ribosomes changing frame. In some cases programmed frameshifting is utilized to produce two different length products. One example is in decoding many mammalian retroviruses, where the GagPol fusion product is produced by frameshifting near the end of the gag gene, enabling ribosomes to enter the pol gene. A second example we are studying is in decoding the E. coli dnaX gene where a specific frameshift yields a second product which is in a 1:1 ratio with the product of standard decoding and both are subunits of DNA polymerase III. In other instances programmed frameshifting is used for autoregulatory purposes. Our efforts on this class are focused on mammalian antizyme where frameshifting serves as a sensor for cellular polyamine levels. In collaboration with Ray Gesteland in this department, we are investigating the sequences responsible for the different types of frameshifting, the mechanisms involved and the biological consequences. Recent dramatic advances in atomic level resolution knowledge of ribosome structure will aid our mechanistic studies and the deluge of genome sequence information is helping find new cases and assess the generality of utilization of non-standard decoding.
Another type of non-standard decoding we are studying is the redefinition of certain stop codons either to specify the 21st encoded amino acid selenocysteine, or with a certain efficiency a standard amino acid (glutamine or tryptophan). A particular sequence context in important for the redefinition. In decoding Murine Leukemia virus it is a 3' pseudoknot (see figure) whereas for mammalian selenocysteine the special sequence is in the 3' untranslated region.
In collaboration with Dr. K. Flanigan we are also studying drug induced readthrough of premature stop codons as a prelude to tests for the amelioration of symptoms of a subset of human genetic disease.
References
1. Atkins JF, Wills NM, Loughran G, Wu C-Y, Parsawar K, Ryan MD, Wang CH, Nelson CC (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, In Press
2. Ivanov IP, Atkins JF (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. 35:1842-58
3. Wills NM, Moore B, Hammer A, Gesteland RF, Atkins JF (2006) A functional -1 ribosomal frameshift signal in human paraneoplastic MA 3 gene. J. Biol. Chem. 281:7082-7088
4. Baranov PV, Fayet O, Hendrix RW, Atkins JF (2006) Recoding in bateriophages and bacterial IS elements. Trends in Genetics 22:174-181
5. Ivanov IP, Gesteland RF, Atkins JF (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
6. Gesteland RF, Cech TR, Atkins JF (2006) Editors 3 rd edition of the Cold Spring Harbor Laboratory Press monograph "The RNA World"
7. Howard MT, Aggarwal G, Anderson C, Khatri S, Flanigan K, Atkins JF (2005) Recoding elements located adjacent to a subset of eukaryal selenocysteine-specifying UGA codons. EMBO J. 24:1596-1607
8. Gurvich OL, Baranov PV, Gesteland RF, Atkins JF (2005) Expression levels influence ribosomal frameshifting at the tandem rare arginine codons AGG_AGG and AGA_AGA in Escherichia coli . J. Bact., In Press
9. Baranov PV, Hammer AW, Zhou J, Gesteland RF, Atkins JF (2005) Transcriptional slippage in bacteria: distribution in sequenced genomes and utilization in IS element gene expression. Genome Biology 6, R25 (9 pages)
10. Baranov PV, Henderson CM, Anderson CB, Gesteland RF, Atkins JF, Howard MT (2005) Programmed ribosomal frameshifting in decoding the SARS-CoV genome. Virology 332:498-510
11. Bucklin DJ, Wills NM, Gesteland RF, Atkins JF (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
