Refining the genetic alphabet: a late-period selection pressure?

The transition from genomic ribonucleic acid (RNA) to deoxyribonucleic acid (DNA) in primitive cells may have created a selection pressure that refined the genetic alphabet, resulting from the global weakening of the N-glycosyl bonds. Hydrolytic rupture of these bonds, termed deglycosylation, leaves an abasic site that is the single greatest threat to the stability and integrity of genomic DNA. The rates of deglycosylation are highly dependent on the identity of the nucleobases. Modifications made to the bases, such as deamination, oxidation, and alkylation, can further increase deglycosylation reaction rates, suggesting that the native bases provide optimum N-glycosyl bond stability. To protect their genomes, cells have evolved highly specific enzymes called glycosylases, associated with DNA repair, that detect and remove these damaged bases. In RNA, however, the occurrence of many of these modified bases is deliberate. The dichotomous behavior that cells exhibit toward base modifications may have originated in the RNA world. Modified bases would have been advantageous for the functional and structural repertoire of catalytic RNAs. Yet in an early DNA world, the utility of these heterocycles was greatly diminished, and their presence posed a distinct liability to the stability of cells' genomes. A natural selection for bases exhibiting the greatest resistance to deglycosylation would have ensured the viability of early DNA life, along with the recruitment of DNA repair.