Translational frameshift

Translational frameshifting or ribosomal frameshifting refers to an alternate process of protein translation. Normally, a protein is translated from one end of the template to the other, generally from the 3' to the 5' end (or 5' to 3' ends of the newly translated strand). However, certain organisms may exhibit a change or shift in the ribosomes frame when translating the genetic code. This is deemed translational or ribosomal frameshifting [Léger M, Dulude D, Steinberg SV, Brakier-Gingras L. "The three transfer RNAs occupying the A, P and E sites on the ribosome are involved in viral programmed -1 ribosomal frameshift." Nucleic Acids Res. 2007;35(16):5581-92. Epub 2007 Aug 17.] .

Process overview

Proteins are translated unidirectionally by reading tri-nucleotides on the mRNA strand also known as codons. Therefore, a shift of any number of nucleotides that is not divisible by 3 in the reading frame will result in subsequent codons to be read completely differently [Ivanov IP, Atkins JF. "Ribosomal frameshifting in decoding antizyme mRNAs from yeast and protists to humans: close to 300 cases reveal remarkable diversity despite underlying conservation." Nucleic Acids Res. 2007;35(6):1842-58. Epub 2007 Mar 1. Review.] . This effectively changes the ribosomal reading frame. For example, the following sentence when read from the beginning makes sense to a reader:

Start|THE CAT AND THE MAN ARE FAT ...
Start|123 123 123 123 123 123 123 ...

However, changing the reading frame by say shifting the first reading up one letter between the T and H on the first word:

T|Start|HEC ATA NDT HEM ANA REF AT... -|Start|123 123 123 123 123 123 12...

Now the sentence makes absolutely no sense. In the case of a translating ribosome, a frameshift can result in nonsense being created after the frameshift or a completely different protein being created after the frameshift. When referring to translational frameshifting, the latter is always inferred, the former being a usual unfortunate result of a point mutation such as a deletion.

Controlling mechanisms

The main differences between a frameshift as a result of mutation and a frameshift as a result of ribosomal frameshifting is that there are a few mechanisms used to control the latter. All are based on the fact that ribosomes do not translate proteins at a steady rate regardless of the sequence. There are certain codons that take longer to translate because there are not equal amounts of dNTP's of that particular codon in the cytosol [de Crécy-Lagard V. "Identification of genes encoding tRNA modification enzymes by comparative genomics." Methods Enzymol. 2007;425:153-83. Review.] . Hence there exists sequences known as "choke points" (small sections of harder to find codons, resulting in a slowed ribosome translation) and "slippery sequences" (small sections of very easily accessible codons, resulting in a quick ribosome translation) that control the rate of ribosomal frameshifting. Slippery sequences can potentially make the reading ribosome "slip" and skip a number of nucleotides (usually only 1) and read a completely different frame thereafter. Choke points reduce the probability of this happening [Green L, Kim CH, Bustamante C, Tinoco I Jr. "Characterization of the Mechanical Unfolding of RNA Pseudoknots." J Mol Biol. 2007 May 26] .

Examples

This type of frameshifting may be programmed to occur at particular recoding sites and is important in some viruses (e.g. SARS, HIV [McNaughton BR, Gareiss PC, Miller BL. "Identification of a selective small-molecule ligand for HIV-1 frameshift-inducing stem-loop RNA from an 11,325 member resin bound dynamic combinatorial library." J Am Chem Soc. 2007 Sep 19;129(37):11306-7. Epub 2007 Aug 28.] ) and some cellular genes (e.g. "prfB" a release factor). Its use is primarily for compacting more genetic information into a shorter amount of genetic material.

Literature