3'-terminal tRNA-like structure, not the bacteriophage-encoded catalytic subunit (Blumenthal and Carmichael, 1979). For tRNA to evolve from template to primer, the replication enzyme would consist—like Qß replicase—of two domains, one catalytic and the other recognizing the 3'-terminal tRNA-like tag. The relative orientation of these two domains would then determine whether the tRNA was used as template or as primer. The remarkable ability of the Mauriceville reverse transcriptase to use RNA either as primer or as template, at least in vitro, suggests that the transition from template to primer may have been straightforward (Wang and Lambowitz, 1993).

A Functional Phylogeny for the Evolution of tRNA in Replication: RNA Genomes to Modern DNA Telomeres. The function of tRNA in the replication of RNA genomes and transitional genomes leads us to propose a phylogeny for the evolution of tRNA in replication. As shown in Figure 4, tRNA-like structures first arose in ancient RNA genomes, where they served as templates for the initiation of replication and also functioned as primitive telomeres. These tRNA-like structures persisted during the evolution of DNA, and they are immortalized today in transitional genomes, RNA genomes that replicate via a DNA intermediate. In the transitional genomes, tRNAs functioned first as template and later as primer for synthesis of a cDNA copy by a reverse transcriptase encoded by the genomic RNA itself.

The role of tRNA in replication is not restricted to viruses and extrachromosomal elements but extends to cellular chromosomes as well. The termini of modern chromosomes are replenished by an enzyme called telomerase, which adds species-specific TnGm repeats, one nucleotide at a time, to an appropriate TnGm primer (reviewed by Blackburn, 1991). Telomerase is a ribonucleoprotein, and its RNA component serves as a built-in template for sequence addition by the reverse transcriptase-like protein subunit. In the Tetrahymena telomerase, for example, a built-in template containing the sequence 5'-CA2C4A2 specifies addition of 5'-T2G4 telomeric repeats. There is an uncanny resemblance between the action of telomerase and the copying of the reiterated CCACCA terminus of a tRNA-like genomic tag by the Mauriceville reverse transcriptase. Moreover, the Mauriceville reverse transcriptase can, like telomerase, initiate at an internal CCA sequence by using a DNA primer (Wang and Lambowitz, 1993). The genomic tag hypothesis suggests that telomere addition can be viewed, from an evolutionary perspective, as abortive replication. Furthermore, if ancient tRNA-like structures were the predecessors of the built-in template in contemporary telomerases, it would explain why modern telomere sequences are variations on a CnAm repeat motif.

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