John F. Atkins
Research Professor of Human Genetics
B.A. Dublin University
Ph.D. Dublin University
Sc.D. Dublin University
John Atkin's PubMed Literature Search
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 Drs. M.T. Howard and 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. Firth AE, Atkins JF (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
2. Wills NM, O’Connor M, Nelson CC, Rettberg CC, Huang WM, Gesteland RF, Atkins JF (2008) Translational bypassing without peptidyl-tRNA anticodon scanning of coding gap mRNA. EMBO J. 27:2533-2544
3. Ivanov IP, Loughran G, Atkins JF (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
4. Firth AE, Chung BYW, Fleeton MN, Atkins JF (2008) Discovery of frameshifting in Alphavirus 6K resolves a 20-year enigma. Virol. J. 5:108
5. Atkins JF, Ryan MD (2008) Foot and Mouth’s Achilles’ heel? Nature Biotech. 26:1335-1336
6. Chung BYW, Miller WA, Atkins JF, Firth A (2008) An overlapping essential gene in the Potyviridae. Proc. Natl. Acad. Sci USA 105:5897-5902
7. Atkins JF, Baranov PV (2007) Duality in the genetic code. Nature 448:1004-1005
8. Gesteland RF, Cech TR, Atkins JF (2006) Editors 3rd edition of the Cold Spring Harbor Laboratory Press monograph “The RNA World” [Available for free at: http://rna.cshl.edu]
