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The high fidelity of DNA polymerase is critical for the faithful replicationof genomic DNA. Several approaches were proposed to quantify the fidelity ofDNA polymerase. Direct measurements of the error frequency of the replicationproducts definitely give the true fidelity but turn out very hard to implement.Two biochemical kinetic approaches, the steady-state assay and thetransient-state assay, were then suggested and widely adopted. In these assays,the error frequency is indirectly estimated by using the steady-state or thetransient-state kinetic theory combined with the measured kinetic rates.However, whether these indirectly estimated fidelities are equivalent to thetrue fidelity has never been clarified theoretically, and in particular thereare different strategies to quantify the proofreading efficiency of DNAP butoften lead to inconsistent results. The reason for all these confusions is thatit's mathematically challenging to formulate a rigorous and general theory ofthe true fidelity. Recently we have succeeded to establish such a theoreticalframework. In this paper, we develop this theory to make a comprehensiveexamination on the theoretical foundation of the kinetic assays and therelation between fidelities obtained by different methods. We conclude thatwhile the steady-state assay and the transient-state assay can always measurethe true fidelity of exonuclease-deficient DNA polymerases, they only do so forexonuclease-efficient DNA polymerases conditionally (the proper way to usethese assays to quantify the proofreading efficiency is also suggested). Wethus propose a new kinetic approach, the single-molecule assay, whichindirectly but precisely characterizes the true fidelity of eitherexonuclease-deficient or exonuclease-efficient DNA polymerases.

A critical survey on the kinetic assays of DNA polymerase fidelity from a new theoretical perspective