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How DNA polymerases catalyse replication and repair with contrasting fidelity

Abstract

DNA polymerases were named for their function of catalysing DNA replication, a process that is necessary for growth and propagation of life. DNA involving Watson–Crick base-pairing can be synthesized with high fidelity, the structural and mechanistic origins of which have been investigated for many decades. Despite this, new chemical insights continue to be uncovered, including recent findings that may explain newly discovered functions for many DNA polymerases in DNA repair and mutation. Some of these reactions involve non-Watson–Crick base-pairing. In addition, certain DNA polymerases have been engineered for a wide variety of applications in biotechnology and biomedicine. This Review describes the molecular basis for the diverse and contrasting functions of different DNA polymerases, providing an up-to-date understanding of how these tasks are accomplished and the means by which we can benefit from them.

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Figure 1: Polymerase fidelity.
Figure 2: Mechanism of phosphodiester bond formation.
Figure 3: Nucleobases in various ionization states and/or conformations.
Figure 4: Structural and energetic differences near the transition state of the nucleotidyl transfer mediated by Pol β.
Figure 5: Polymerases overcome Watson–Crick pairing by engaging in multiple interactions with substrates.
Figure 6: Certain polymerases, by virtue of the size and nature of their active sites, are active in translesion syntheses.

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Acknowledgements

The authors acknowledge financial support from the Ministry of Science and Technology (Grant Nos MOST103-2113-M-001-016-MY3, MOST105-0210-01-12-01 and MOST106-0210-01-15-04) to M.-D.T. and a US National Institutes of Health intramural grant (DK036146-08) to W.Y.

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Correspondence to Ming-Daw Tsai.

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Wu, WJ., Yang, W. & Tsai, MD. How DNA polymerases catalyse replication and repair with contrasting fidelity. Nat Rev Chem 1, 0068 (2017). https://doi.org/10.1038/s41570-017-0068

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