2. Academic Validation
  3. Polyploidy mitigates the impact of DNA damage while simultaneously bearing its burden

Polyploidy mitigates the impact of DNA damage while simultaneously bearing its burden

  • Cell Death Discov. 2024 Oct 13;10(1):436. doi: 10.1038/s41420-024-02206-w.
Kazuki Hayashi 1 2 3,  Kisara Horisaka 1,  Yoshiyuki Harada 1 4,  Yuta Ogawa 1 3,  Takako Yamashita 1 3,  Taku Kitano 1 3 5,  Masahiro Wakita 1,  Takahito Fukusumi 2,  Hidenori Inohara 2,  Eiji Hara 6 7,  Tomonori Matsumoto 8 9
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • 2 Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
  • 3 Laboratory of Ploidy Pathology, Graduate School of Frontier Bioscicences, Osaka University, Osaka, Japan.
  • 4 Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
  • 5 Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 6 Department of Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. ehara@biken.osaka-u.ac.jp.
  • 7 Laboratory of Aging Biology, Immunology Frontier Research Center, Osaka University, Osaka, Japan. ehara@biken.osaka-u.ac.jp.
  • 8 Department of Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. matsumoto.tomonori.fbs@osaka-u.ac.jp.
  • 9 Laboratory of Ploidy Pathology, Graduate School of Frontier Bioscicences, Osaka University, Osaka, Japan. matsumoto.tomonori.fbs@osaka-u.ac.jp.
PMID: 39397009 DOI: 10.1038/s41420-024-02206-w
Abstract

Polyploidy is frequently enhanced under pathological conditions, such as tissue injury and Cancer in humans. Polyploidization is critically involved in Cancer evolution, including Cancer initiation and the acquisition of drug resistance. However, the effect of polyploidy on cell fate remains unclear. In this study, we explored the effects of polyploidization on cellular responses to DNA damage and cell cycle progression. Through various comparisons based on ploidy stratifications of cultured cells, we found that polyploidization and the accumulation of genomic DNA damage mutually induce each Other, resulting in polyploid cells consistently containing more genomic DNA damage than diploid cells under both physiological and stress conditions. Notably, despite substantial DNA damage, polyploid cells demonstrated a higher tolerance to its impact, exhibiting delayed cell cycle arrest and reduced secretion of inflammatory cytokines associated with DNA damage-induced senescence. Consistently, in mice with ploidy tracing, hepatocytes with high ploidy appeared to potentially persist in the damaged liver, while being susceptible to DNA damage. Polyploidy acts as a reservoir of genomic damage by mitigating the impact of DNA damage, while simultaneously enhancing its accumulation.

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