Molecular Genetics 

Facts

• Frameshifting occurs at several positions during translation of MS2 bacteriophage RNA. A frame shift near the end of the COAT gene leads to premature termination in close proximity to the initiation codon of the lysis gene. Other frameshifts lead to COAT-LYSIS fusions and longer than normal synthetase polypeptides.

• Translation of some retroviral (HIV-1, for example) mRNAs, requires a ribosomal frameshifting event to translate the pol ORF which follows gag.
• In MMTV, two frameshifting events occur, the first between gag and the protease domain of pol, the second between the latter and the remainder of pol.
• The frameshifts require a 7 nucleotide signal at the site of frameshifting and a stem-loop structure. An RNA pseudoknot is involved.
• Frameshifting is due to slippage rather than reading of a dinucleotide as a codon, since mutation of UUAUA to UUUUA results in a change in coding from Leu Ile to Phe Leu.

• Phenotypic revertants of bacteria and yeast with frameshift mutations are often due to extragenic second-site mutations. These mutations are often in tRNA genes. The tRNA mutation creates an anticodon that recognizes a four base codon, restoring the reading frame of a one base insertion mutation.
• tRNA Phe can act as a frameshifting tRNA without mutation if the UUU codon it recognizes is in a stretch of five or more U's.
• The gene for the E.coli factor required for termination of protein synthesis at UGA codons, RF2, has an internal UGA stop codon.
• In the presence of insufficient RF2, termination at this UGA is suppressed by +1 frameshifting. In the presence of sufficient RF2, premature termination of RF2 synthesis occurs.

Interpretations

• Most mRNAs are translated precisely three nucleotides at a time.
• Yet, translational frameshifting is a frequent strategy used in expression of genes of viruses, related pathogens, and related genetic elements (eg. transposable elements).
• Shifts in reading frame due to transcriptional or RNA processing events also occur.
• Since translational frameshifting requires a complex signal consisting of a nucleotide sequence and a complex RNA secondary structure element, it is unlikely that frameshifting will occur accidentally during the translation of most mRNAs.
• The efficiency of the frameshifting signal determines the stoichiometric ratio of the two products.
• In bacteria, termination suppression by frameshifting provides a homeostatic gene expression regulation mechanism.

Further information

• Reversion mutations at second sites are called suppressor mutations. The tRNAs responsible for such reversions are known as suppressor tRNAs.
• Some retroviruses use a different strategy, termination suppression, to produce gag-pol fusion polypeptides.
• Frameshifting occurs during translation of some non-viral and non-transposable element mRNAs.
• For example, the active product of the EST3 gene, required to maintain telomere length in Saccharomyces cerevisiae, is made by a +1 ribosomal frameshift.  
• The S. cerevisiae ABP140 gene, encoding an actin filament binding protein, is translated by a +1 frame shift.
• Antizyme (rev)
  • is a protein that inhbits the further accumulation of polyamines. I does so by
    • inhibiting ornithine decarboxylase (ODC), a key enzyme of polyamine synthesis;
    • in mammals, hastening proteasome destruction of ODC;
    • inhibiitng polyamine uptake by cells;
    • stimulating polyamine export from cells.
  • synthesis requires a spermine induced +1 frame shift in translation. A regulatory loop producing constant levels of polyamines results.
• The dnaX gene of E. coli produces a mRNA that is translated into equal amounts of two polypeptides, one longer than the other, and each of which is incorporated stoichiometrically into the structure of DNA polymerase III. One subunit serves the leading strand, the other the lagging strand. The longer polypeptide is produced by -1 frameshift during translation.
• Shine Dalgarno sequences just 5' of the shifty sequence stimulate frameshifting in bacteria.
• The structure of the pseudoknot stimulating frameshifting in mouse mammary tumor virus has been determined (ref).

This is page 2414 of Molecular Genetics by Ulrich Melcher, © 1997, 1998, 2000, 2004