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Linker-mediated conformational coupling drives lesion recognition in MutY glycosylase

Hyeonjun Kim1, Manho Lim1, Youngshang Pak1

  • 1Department of Chemistry and Institute of Functional Materials, Pusan National University, Busan 46241, South Korea.

Nucleic Acids Research
|May 11, 2026
PubMed

Insights

MutY glycosylase repairs oxidative DNA damage by removing adenine mispaired with 8-oxoguanine (8OG). A flexible linker guides synchronized base rotations, ensuring accurate lesion recognition and genome stability.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Genome stability is crucial for preventing mutations.
  • Oxidative DNA damage, specifically 8-oxoguanine (8OG), can lead to G:C→T:A transversions.
  • MutY glycosylase is essential for excising adenine mispaired with 8OG.

Purpose of the Study:

  • To elucidate the dynamic mechanism by which MutY glycosylase recognizes oxidative DNA damage.
  • To understand the role of the interdomain linker in lesion recognition.
  • To map the free energy landscape of MutY's DNA repair process.

Main Methods:

  • Large-scale enhanced-sampling molecular dynamics simulations.
  • Free energy landscape analysis.
  • Structural and mechanistic modeling of enzyme-DNA interactions.

Main Results:

  • Identified a dominant pathway for adenine excision from 8OG.
  • Demonstrated synchronized glycosidic rotations of adenine and 8OG.
  • Revealed the critical role of a flexible interdomain linker in coordinating base flipping, isomerization, and domain rearrangements.
  • Characterized the transition from encounter complex to lesion recognition complex.

Conclusions:

  • The flexible interdomain linker orchestrates a unified process for adenine recognition and excision.
  • This mechanism ensures accurate lesion interrogation and maintains genome integrity.
  • Provides a new mechanistic framework for MutY and related glycosylases with flexible linkers.

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