Hayashi Kazuki, Horisaka Kisara, Harada Yoshiyuki, Ogawa Yuta, Yamashita Takako, Kitano Taku, Wakita Masahiro, Fukusumi Takahito, Inohara Hidenori, Hara Eiji, Matsumoto Tomonori
Department of Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Cell Death Discov. 2024 Oct 13;10(1):436. doi: 10.1038/s41420-024-02206-w.
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.
在诸如人体组织损伤和癌症等病理条件下，多倍体现象常常会增强。多倍体化在癌症演变过程中起着关键作用，包括癌症的起始以及耐药性的获得。然而，多倍体对细胞命运的影响仍不明确。在本研究中，我们探究了多倍体化对细胞应对DNA损伤及细胞周期进程的影响。通过基于培养细胞倍性分层的各种比较，我们发现多倍体化与基因组DNA损伤的积累相互诱导，导致在生理和应激条件下，多倍体细胞始终比二倍体细胞含有更多的基因组DNA损伤。值得注意的是，尽管存在大量DNA损伤，多倍体细胞对其影响表现出更高的耐受性，表现为细胞周期阻滞延迟以及与DNA损伤诱导的衰老相关的炎性细胞因子分泌减少。同样，在具有倍性追踪的小鼠中，高倍性的肝细胞似乎有可能在受损肝脏中持续存在，同时易受DNA损伤影响。多倍体通过减轻DNA损伤的影响，同时增强其积累，从而充当基因组损伤的储存库。
