A reexamination of the nucleotide incorporation fidelity of DNA polymerases.
Intensive study has been devoted to understanding the kinetic and structural bases underlying the exceptionally high fidelity (low error frequencies) of the typical DNA polymerase. Commonly proposed explanations have included (i) the concept of fidelity check points, in which the correctness of a nascent base pair match is tested at multiple points along the reaction pathway, and (ii) an induced-fit fidelity enhancement mechanism based on a rate-limiting, substrate-induced conformational change. In this article, we consider the evidence and theoretical framework for the involvement of such mechanisms in fidelity enhancement. We suggest that a "simplified" model, in which fidelity is derived fundamentally from differential substrate binding at the transition state of a rate-limiting chemical step, is consistent with known data and sufficient to explain the substrate selectivity of these enzymes.
Departments of Chemistry and Biochemistry, Biophysics Program, The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA.
Alexander K
AK
Showalter
Ming-Daw
MD
Tsai
D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D009711:Nucleotides / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity; D013816:Thermodynamics
D009711:Nucleotides; D004259:DNA-Directed DNA Polymerase