In crystallo observation of three metal ion promoted DNA polymerase misincorporation

Caleb Chang, Christie Lee Luo and Yang Gao ()
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Caleb Chang: Rice University
Christie Lee Luo: Rice University
Yang Gao: Rice University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Error-free replication of DNA is essential for life. Despite the proofreading capability of several polymerases, intrinsic polymerase fidelity is in general much higher than what base-pairing energies can provide. Although researchers have investigated this long-standing question with kinetics, structural determination, and computational simulations, the structural factors that dictate polymerase fidelity are not fully resolved. Time-resolved crystallography has elucidated correct nucleotide incorporation and established a three-metal-ion-dependent catalytic mechanism for polymerases. Using X-ray time-resolved crystallography, we visualize the complete DNA misincorporation process catalyzed by DNA polymerase η. The resulting molecular snapshots suggest primer 3´-OH alignment mediated by A-site metal ion binding is the key step in substrate discrimination. Moreover, we observe that C-site metal ion binding preceded the nucleotidyl transfer reaction and demonstrate that the C-site metal ion is strictly required for misincorporation. Our results highlight the essential but separate roles of the three metal ions in DNA synthesis.

Date: 2022
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DOI: 10.1038/s41467-022-30005-3

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