The importance of being modified: Tautomeric forms of pyrimidines provide expanded use of the genetic code

RiboEvo Seminar Series

Tautomeric shifts of 5-modified uridines have been established in E. coli tRNA^Val_cmo5UAC as well as in the human cytoplasmic tRNA^Lys3_mcm5s2UUU. These shifts enable the recognition of multiple codons with the wobble base pair in the Watson-Crick geometry suggesting an energetic preference for, and perhaps enhanced efficiency with, this conformation. Thus, modifications at the 5-position of wobble position uridines appear to be a common mechanism for expanding tRNA’s codon recognition. One deviation from the universal code that is particularly interesting is the reading of AUG and the universal isoleucine codon AUA as methionine in both the A- and P-sites of the mitochondrial ribosome of most metazoans. We have established a mechanism by which 5-formylcytidine (f⁵C) at the wobble position of human mitochondrial tRNA^Met (hmtRNA^Met_f5CAU) expands the decoding ability of this tRNA enabling it to read AUA as methionine. We have also found that another modified cytidine can restrict wobble base formation. This underscores the ability of cytidines, as well as uridine, modifications within the anticodon loop to modulate the decoding ability of the tRNA, providing insight into decoding mechanisms and evolution of the genetic code.

For more information contact Prof. Loren Williams (404-894-9752).