Termination Of Translation

14.1. Termination Codons

The ribosome reads mRNA triplet by triplet and elongates the polypeptide chain until it comes across one of the following codons: UAA, UAG, or UGA. None of these triplets possess a cognate aminoacyl-tRNA; they all stop translation. Thus, they serve as termination codons (Brenner et al., 1965, 1967). UAA is the most frequently used of these codons, whereas the use of UAG is the rarest.

The termination codon is always present at the end of the coding region of any naturally occurring mRNA. Termination codons are sometimes present in tandem, e.g., at the end of the MS2 bacteriophage coat protein cistron, where the termination codon UAA is followed by UAG (see Section 16.4.1). It is interesting that in Eukaryotes a termination codon is often followed by a purine nucleotide, and generally the tetranucleotide stop signals UAA(A/G) and UGA(A/G) are preferred. In bacteria (E. coli), the most preferred termination sequences are UAAU and UAAG (for review, see Tate & Brown, 1992).

It should be noted that triplets UAA, UAG, and UGA are found far more often in wrong reading frames within mRNA coding regions than in the correct reading frame, where, as a rule, only one such triplet per coding sequence is present. Therefore an accidental frame shift in the course of elongation does not usually result in the synthesis of a long wrong polypeptide and generally leads to an early termination of this mistranslation. The frequency of termination triplets is also high in the noncoding mRNA regions, including the intercistronic regions of polycistronic mRNAs.

The termination triplet may appear in the reading frame of the mRNA coding region as a result of mutation. For example, a change of G to A in the tryptophan codon UGG results in the appearance of either UAG or UGA; a change of C to U in the glutamine codons CAA or CAG results in either UAA or UAG. Such mutations are referred to as nonsense mutations; the appearance of UAG is called the "amber" mutation, UAA the "ochre" mutation, and UGA the "opal" mutation. In contrast to the usual point mutations which result in the replacement of the amino acid in the synthesized polypeptide, these mutations lead to premature termination, which takes place at just the point where the nonsense codon appears. Another mutation changing the anticodon of some tRNA species in such a way that it becomes complementary to the nonsense codon may result in the suppression of the nonsense mutation; e.g., tyrosine tRNA, in which the anticodon GUA is changed into CUA, recognizes the termination codon UAG and thus suppresses the amber mutations.

Translation may proceed with errors, including ones in which the normal termination codon at the end of the mRNA coding sequence is recognized by the tRNA with an anticodon having partial complementarity to it (for reviews, see Eggertsson & Soell, 1988; Valle & Morsh, 1988). Thus, the normal tryptophan tRNA with its anticodon CCA can occasionally recognize the termination UGA codon, or glutamine tRNA with anticodon CUG or UUG may interact with termination codon UAG or UAA, respectively. A minor tyrosine tRNA with anticodon GYA isolated from plants and insects has been shown to recognize termination codon UAG. Two leucine tRNAs harboring anticodons CAA and CAG isolated from calf liver have been reported to be capable of interacting with termination codon UAG. A lysyl-tRNA of yeast has been also reported to insert its amino acid residue in response to UAG codon. All this results in a message being occasionally read through and a longer polypeptide being synthesized. The formation of such longer products, in addition to the normal translation product, has often been observed in studies of protein synthesis both in vivo and in vitro. Similar mechanisms underlie the formation of small amounts of the normal product in the nonsense mutants ("leakage", see Section 10.4.2).

The codon UGA is the "weakest" among the three termination codons: it can be read-through by a translating ribosome most frequently, seemingly due to its recognition by tryptophanyl-tRNA (Hirsh, 1971). In some cases this termination codon is specially used in nature, in order to form a small amount of a physiologically important protein from a read-through product, in addition to the main protein product whose translation is terminated by this codon. Such situation is observed in the case of QP phage RNA translation (Fig. 14.1): coat protein cistron is ended by the termination codon UGA which is occasionally

Coat protein

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