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Related Experiment Video

Updated: Jun 5, 2026

Single-Molecule Real-Time Visualization of DNA Unwinding by CMG Helicase

Single-Molecule Real-Time Visualization of DNA Unwinding by CMG Helicase

Published on: September 27, 2024

Replication infidelity via a mismatch with Watson-Crick geometry.

Katarzyna Bebenek¹, Lars C Pedersen, Thomas A Kunkel

¹Laboratory of Molecular Genetics, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

Proceedings of the National Academy of Sciences of the United States of America

|January 15, 2011

Summary

DNA polymerase can insert mismatched bases with Watson-Crick geometry, supporting early mutation theories. This finding suggests a shared mechanism for inserting both correct and incorrect nucleotides during DNA replication.

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Last Updated: Jun 5, 2026

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Published on: September 27, 2024

Proofreading and DNA Repair Assay Using Single Nucleotide Extension and MALDI-TOF Mass Spectrometry Analysis

Proofreading and DNA Repair Assay Using Single Nucleotide Extension and MALDI-TOF Mass Spectrometry Analysis

Published on: June 19, 2018

Area of Science:

Molecular Biology
Biochemistry
Genetics

Background:

DNA polymerases typically prevent errors during replication.
Previous research lacked structural evidence for DNA polymerases forming natural mismatches with Watson-Crick geometry.
Tautomerization or ionization of bases can lead to mispairing.

Purpose of the Study:

To provide structural evidence of a DNA polymerase forming a natural base-base mismatch with Watson-Crick-like geometry.
To investigate the catalytic mechanism of nucleotide insertion, including mismatches.

Main Methods:

X-ray crystallography of a human DNA polymerase lambda (Pol λ) variant.
Analysis of enzyme active site geometry during nucleotide misinsertion.
pH dependence studies to assess base ionization.

Main Results:

A crystal structure revealed a human DNA polymerase λ variant poised to misinsert dGTP opposite a template T with Watson-Crick geometry.
The active site geometry supported catalysis for this mismatch, similar to correct base pairing.
pH dependence suggested base ionization as a contributing factor to misinsertion.

Conclusions:

The study provides the first structural evidence for a DNA polymerase forming a natural mismatch with Watson-Crick geometry.
Results support the hypothesis that base substitutions can arise from Watson-Crick-like mismatches.
A common catalytic mechanism for inserting correct and incorrect nucleotides is suggested.