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Replication infidelity via a mismatch with Watson-Crick geometry.

Bebenek K, Pedersen LC, Kunkel TA
Proc Natl Acad Sci U S A 108 1862-7 (2011)
Related entries: 3pml, 3pnc

Cited: 91 times
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Abstract

In describing the DNA double helix, Watson and Crick suggested that "spontaneous mutation may be due to a base occasionally occurring in one of its less likely tautomeric forms." Indeed, among many mispairing possibilities, either tautomerization or ionization of bases might allow a DNA polymerase to insert a mismatch with correct Watson-Crick geometry. However, despite substantial progress in understanding the structural basis of error prevention during polymerization, no DNA polymerase has yet been shown to form a natural base-base mismatch with Watson-Crick-like geometry. Here we provide such evidence, in the form of a crystal structure of a human DNA polymerase λ variant poised to misinsert dGTP opposite a template T. All atoms needed for catalysis are present at the active site and in positions that overlay with those for a correct base pair. The mismatch has Watson-Crick geometry consistent with a tautomeric or ionized base pair, with the pH dependence of misinsertion consistent with the latter. The results support the original idea that a base substitution can originate from a mismatch having Watson-Crick geometry, and they suggest a common catalytic mechanism for inserting a correct and an incorrect nucleotide. A second structure indicates that after misinsertion, the now primer-terminal G • T mismatch is also poised for catalysis but in the wobble conformation seen in other studies, indicating the dynamic nature of the pathway required to create a mismatch in fully duplex DNA.

Reviews - 3pmn mentioned but not cited (1)

  1. Structure-function studies of DNA polymerase λ. Bebenek K, Pedersen LC, Kunkel TA. Biochemistry 53 2781-2792 (2014)

Articles - 3pmn mentioned but not cited (2)

  1. Replication infidelity via a mismatch with Watson-Crick geometry. Bebenek K, Pedersen LC, Kunkel TA. Proc. Natl. Acad. Sci. U.S.A. 108 1862-1867 (2011)
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Reviews citing this publication (6)

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  4. Recognition of Watson-Crick base pairs: constraints and limits due to geometric selection and tautomerism. Westhof E, Yusupov M, Yusupova G. F1000Prime Rep 6 19 (2014)
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  6. Structural Insights Into Tautomeric Dynamics in Nucleic Acids and in Antiviral Nucleoside Analogs. Fedeles BI, Li D, Singh V. Front Mol Biosci 8 823253 (2021)

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