Programmed translational frameshifting

Abstract

Translating ribosomes maintain their reading frame with extreme accuracy. However, certain RNA sequences program the ribosome to alter the reading frame efficiently to allow for the expression of alternative translational products. Site which cause the ribosome to shift frames, termed programmed frameshift sites, occur in organisms from bacteria to higher eukaryotes. Mechanistically, the frameshift events are very diverse. Ribosomes may shift frames 1 base in the leftward, or -1, direction, 1 base in the rightward, or +1, direction, and even over dozens of nucleotides in the rightward direction, an event termed a translational hop. By studying the sequence requirements of such sites, the primary sequence of the peptides produced, and the effect of site-specific mutations, researchers have defined the rules of programmed frameshifting at a large number of sites of all three types. Although the detailed mechanisms differ, the sites all conform to a general pattern. Programmed frameshifting occurs when the ribosome transiently pauses during elongation with a sequence in the decoding sites of the ribosome which predisposes it to shift frames. In almost all cases, this predisposition results from the ability of tRNAs to reposition themselves on cognate or near-cognate codons in the new reading frame. However, this is not a universal requirement, since at least two programmed +1 frameshifts probably occur without tRNA slippage. These events occur when the mRNA sequence of the frameshift site manipulates the frame maintenance mechanism of the ribosome to increase drastically the probability of frame disruption. They may therefore be used as tools to probe this mechanism.