SURVEY AND SUMMARY Decoding the genome: a modi®ed view

Transfer RNA's role in decoding the genome is critical to the accuracy and ef®ciency of protein synthesis. Though modi®ed nucleosides were identi®ed in RNA 50 years ago, only recently has their importance to tRNA's ability to decode cognate and wobble codons become apparent. RNA modi®cations are ubiquitous. To date, some 100 different posttranslational modi®cations have been identi®ed. Modi®cations of tRNA are the most extensively investigated; however, many other RNAs have modi®ed nucleosides. The modi®cations that occur at the ®rst, or wobble position, of tRNA's anticodon and those 3¢-adjacent to the anticodon are of particular interest. The tRNAs most affected by individual and combinations of modi®cations respond to codons in mixed codon boxes where distinction of the third codon base is important for discriminating between the correct cognate or wobble codons and the incorrect near-cognate codons (e.g. AAA/G for lysine versus AAU/C asparagine). In contrast, other modi®cations expand wobble codon recognition, such as U ́U base pairing, for tRNAs that respond to multiple codons of a 4-fold degenerate codon box (e.g. GUU/A/C/G for valine). Whether restricting codon recognition, expanding wobble, enabling translocation, or maintaining the messenger RNA, reading frame modi®cations appear to reduce anticodon loop dynamics to that accepted by the ribosome. Therefore, we suggest that anticodon stem and loop domain nucleoside modi®cations allow a limited number of tRNAs to accurately and ef®ciently decode the 61 amino acid codons by selectively restricting some anticodon±codon interactions and expanding others.