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Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots

Author

Listed:
  • Pallavi Kompella

    (Dell Pediatric Research Institute)

  • Guliang Wang

    (Dell Pediatric Research Institute)

  • Russell E. Durrett

    (The University of Texas at Austin)

  • Yanhao Lai

    (Florida International University)

  • Celeste Marin

    (Florida International University)

  • Yuan Liu

    (Florida International University)

  • Samy L. Habib

    (South Texas Veterans Health Care System)

  • John DiGiovanni

    (Dell Pediatric Research Institute)

  • Karen M. Vasquez

    (Dell Pediatric Research Institute)

Abstract

Obesity is associated with increased cancer risk, yet the underlying mechanisms remain elusive. Obesity-associated cancers involve disruptions in metabolic and cellular pathways, which can lead to genomic instability. Repetitive DNA sequences capable of adopting alternative DNA structures (e.g., H-DNA) stimulate mutations and are enriched at mutation hotspots in human cancer genomes. However, it is not known if obesity impacts DNA repeat-mediated endogenous mutation hotspots. We address this gap by measuring mutation frequencies in obese and normal-weight transgenic reporter mice carrying either a control human B-DNA- or an H-DNA-forming sequence (from a translocation hotspot in c-MYC in Burkitt lymphoma). Here, we discover that H-DNA-induced DNA damage and mutations are elevated in a tissue-specific manner, and DNA repair efficiency is reduced in obese mice compared to those on the control diet. These findings elucidate the impact of obesity on cancer-associated endogenous mutation hotspots, providing mechanistic insight into the link between obesity and cancer.

Suggested Citation

  • Pallavi Kompella & Guliang Wang & Russell E. Durrett & Yanhao Lai & Celeste Marin & Yuan Liu & Samy L. Habib & John DiGiovanni & Karen M. Vasquez, 2024. "Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50006-8
    DOI: 10.1038/s41467-024-50006-8
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    References listed on IDEAS

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    1. David P. Labbé & Giorgia Zadra & Meng Yang & Jaime M. Reyes & Charles Y. Lin & Stefano Cacciatore & Ericka M. Ebot & Amanda L. Creech & Francesca Giunchi & Michelangelo Fiorentino & Habiba Elfandy & S, 2019. "High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Adela Hruby & Frank Hu, 2015. "The Epidemiology of Obesity: A Big Picture," PharmacoEconomics, Springer, vol. 33(7), pages 673-689, July.
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