structure Efficient ribosomal frameshifting generally requires the presence of an RNA secondary structure to enhance the effects of the slippery sequence. The RNA structure (which can be a stem-loop or pseudoknot) is thought to pause the ribosome on the slippery site during translation, forcing it to relocate and continue replication from the −1 position. It is believed that this occurs because the structure physically blocks movement of the ribosome by becoming stuck in the ribosome mRNA tunnel. This model is supported by the fact that strength of the pseudoknot has been positively correlated with the level of frameshifting for associated mRNA. Below are examples of predicted secondary structures for frameshift elements shown to stimulate frameshifting in a variety of organisms. The majority of the structures shown are stem-loops, with the exception of the ALIL (apical loop-internal loop) pseudoknot structure. In these images, the larger and incomplete circles of mRNA represent linear regions. The secondary "stem-loop" structures, where "stems" are formed by a region of mRNA base pairing with another region on the same strand, are shown protruding from the linear DNA. The linear region of the HIV ribosomal frameshift signal contains a highly conserved UUU UUU A slippery sequence; many of the other predicted structures contain candidates for slippery sequences as well. The mRNA sequences in the images can be read according to a set of guidelines. While A, T, C, and G represent a particular nucleotide at a position, there are also letters that represent ambiguity which are used when more than one kind of nucleotide could occur at that position. The rules of the International Union of Pure and Applied Chemistry (IUPAC) are as follows: These symbols are also valid for RNA, except with U (uracil) replacing T (thymine). Trans-acting elements Small molecules, proteins, and nucleic acids have been found to stimulate levels of frameshifting. For example, the mechanism of a negative feedback loop in the polyamine synthesis pathway is based on polyamine levels stimulating an increase in +1 frameshifts, which results in production of an inhibitory enzyme. Certain proteins which are needed for codon recognition or which bind directly to the mRNA sequence have also been shown to modulate frameshifting levels. MicroRNA (miRNA) molecules may hybridize to a RNA secondary structure and affect its strength. See also Antizyme RNA frameshifting stimulation element Coronavirus frameshifting stimulation element DnaX ribosomal frameshifting element Frameshift mutation HIV ribosomal frameshift signal Insertion