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Aging alters DNA structure-induced genetic instability in mice.

Tonia T Li1, Guliang Wang1, Alexandra M D'Amico1

  • 1Division of Pharmacology and Toxicology, Dell Pediatric Research Institute, College of Pharmacy, The University of Texas at Austin, Austin, TX 78723.

Proceedings of the National Academy of Sciences of the United States of America
|April 7, 2026
PubMed
Summary
This summary is machine-generated.

Aging impacts Z-DNA mutagenicity. While Z-DNA remains mutagenic, age-related decreases in deletions were observed due to reduced DNA repair efficiency and increased apoptosis, offering insight into aging and cancer links.

Keywords:
DNA repairagingalternative DNA structurescancergenetic instability

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Area of Science:

  • Genetics
  • Molecular Biology
  • Aging Research

Background:

  • Repetitive DNA can form non-B DNA structures like Z-DNA, contributing to genetic instability.
  • Z-DNA is linked to age-related diseases including cancer and Alzheimer's.
  • Previous studies confirmed Z-DNA's mutagenicity in mammals.

Purpose of the Study:

  • To investigate the impact of aging on Z-DNA-induced genetic instability.
  • To explore the mechanistic basis of age-related changes in Z-DNA mutagenicity.

Main Methods:

  • Utilized a transgenic mutation reporter mouse model.
  • Compared Z-DNA and B-DNA mutagenicity across different tissues and age groups.
  • Analyzed mutation frequencies (deletions and point mutations) and DNA repair processes.

Main Results:

  • Z-DNA was consistently more mutagenic than B-DNA in all tested tissues.
  • Z-DNA-induced deletion frequencies decreased with age.
  • Point mutation frequencies remained stable across age groups.
  • Cleavage activities on Z-DNA were similar in young and aged mice.

Conclusions:

  • Aging attenuates Z-DNA-induced deletion mutagenesis.
  • Reduced DNA end-joining efficiency and increased apoptosis in aged mice contribute to decreased Z-DNA deletions.
  • Findings provide mechanistic insights into age-associated genetic instability and the aging-cancer connection.