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

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2024-10-13 DOI:10.1038/s41420-024-02206-w

Kazuki Hayashi, Kisara Horisaka, Yoshiyuki Harada, Yuta Ogawa, Takako Yamashita, Taku Kitano, Masahiro Wakita, Takahito Fukusumi, Hidenori Inohara, Eiji Hara, Tomonori Matsumoto

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引用次数: 0

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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多倍体在减轻 DNA 损伤影响的同时，也承受着 DNA 损伤带来的负担。

多倍体经常在病理条件下增强，如人体组织损伤和癌症。多倍体化与癌症的演变，包括癌症的诱发和耐药性的获得密切相关。然而，多倍体对细胞命运的影响仍不清楚。在这项研究中，我们探讨了多倍体化对细胞应对 DNA 损伤和细胞周期进展的影响。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，导致多倍体细胞在生理和应激条件下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，尽管存在大量的DNA损伤，多倍体细胞对其影响表现出更高的耐受性，表现出延迟的细胞周期停滞和减少与DNA损伤诱导的衰老相关的炎症细胞因子的分泌。同样，在进行倍性追踪的小鼠中，倍性高的肝细胞似乎有可能持续存在于受损的肝脏中，同时容易受到DNA损伤。多倍性可以减轻DNA损伤的影响，同时增强DNA损伤的积累，从而成为基因组损伤的储存库。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.