Over the past few years, many groups have attempted to recreate the process of evolution in the test tube — by selecting DNA binding proteins, optimal DNA binding sites, RNA molecules that contort to bind a variety of ligands and so forth. A recent paper (Roth, A. & Breaker, R. Proc. Natl. Acad. Sci. USA 95, 6027–6031, 1998) demonstrates that our appetite for in vitro evolution — and for understanding the origins of life — is not waning and reaffirms that nucleic acids can be much more than just storehouses of information.

Roth and Breaker devised a selection strategy to determine whether a DNA molecule could use an amino acid as a cofactor for cleaving an RNA phosphodiester bond. They chose to try histidine as a cofactor, since it is one of the most common residues in the active sites of protein enzymes. Starting with a random piece of DNA (40 nucleotides long) that had been embedded between two sets of fixed DNA pairing elements, they hoped to give some initial structure to a potential histidine binding site. They succeeded: a set of selected DNAs depend on histidine — and histidine very specifically — to perform the reaction. Under optimal conditions, these deoxyribozymes mediate catalytic rate enhancements of ∼106-fold, on par with the activities of natural self-cleaving ribozymes. Moreover, the pH dependence of the reaction suggests that histidine plays a catalytic role. The pictures to the right show examples of cleavage reactions by HD1, a DNA molecule that was designed based on the results of the selection experiments. In the gel images, the upper band is the 5'-labeled substrate and the lower band is the cleaved product. A different histidine analog (depicted above the gels) was used in each reaction. These and more quantitative results demonstrate that HD1 discriminates effectively against many histidine-related compounds, using only specific histidine analogs as cofactors.

What does this tell us about the origin of life? To speculate wildly, perhaps nucleic acids used such adaptations to coerce protein components into performing chemical reactions. If so, little did they know that their clever cofactors would band together and gradually stage a revolution — taking over many of the duties suspected to be performed by nucleic acids in the prebiotic world. TLS