Frameshift Suppression
The term "frameshift" can have a variety of meanings. Frameshift mutations are those that delete or insert one or a few nucleotides, changing the reading frame of a gene. Frameshift suppressors are genetic changes to elements of the translational machinery that allow ribosomes to read through such a mutation, producing the normal protein despite the genetic alteration. Finally, programmed frameshifts are changes in reading frame induced by specific mRNA sequences.
The most familiar frameshift suppressors are those that alter the structure of tRNAs (Atkins et al.). Most frameshift suppressing tRNAs have an extra nucleotide in their anticodon loop immediately adjacent to or within the anticodon. Suppressible mutations are those that have had a single extra nucleotide in a codon read by the tRNA. The structure of the tRNA and the supressible mutation suggested that suppressor tRNAs induce a +1 frameshift by reading a 4 nucleotide codon.
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In normal decoding the three nucleotide anticodon, e.g. GGG, reads a 3 nt codon, e.g. CCC. After acceptance in the A site of the ribosome and peptide transfer, the new peptidyl-tRNA translocates 3 nt, bringing a new codon into the A site. |
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The prevailing hypothesis, termed the quadruplet decoding model, predicts that the tRNA recognizes a 4 nt codon. After peptide transfer the tRNA would cause a 4 nt translocation, placing a codon in the +1 frame into the A site. This would explain its ability to induce frameshifting. |
During my sabbatical in Dr. Glenn Björk's laboratory at Umeå University in Umeå, Sweden we obtained data incompatible with this model (Qian et al.). Dr. Björk's doctoral students Ji-nong Li and Qiang Qian demonstrated first that modification of the proline inserting frameshift suppressors in the bacterium Salmonella typhimurium precluded their recognizing a 4 nt codon (they actually read by a two-out-of-three mechanism) and that frameshifting was a P site event, probably resulting from peptidyl-tRNA slippage. I showed that frameshifting induced by both proline and glycine suppressors in yeast also occurs in the P site. We proposed a new model for frameshift suppression and predicted that it might be generally applicable to all frameshift suppression (both +1 and -1) and in both prokaryotes and eukaryotes. The mechanism strongly resembles our model of programmed +1 frameshifting in yeast (illustrated below). We are still testing implications of this model.
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In the new model, the suppressor tRNA makes 2 bp with the mRNA and after peptide transfer it can slip +1 (shown) moving a +1 (frame codon into the A site. |