期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.656795
关键词
cytolethal distending toxin; replicative stress; genetic instability; DNA bridge; DNA damage; human colorectal organoid
资金
- La Ligue Contre le Cancer (Haute-Garonne's committee) [ANR-10CESA-0011, ANR-14-CE21-0008]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE21-0008] Funding Source: Agence Nationale de la Recherche (ANR)
The cytolethal distending toxin (CDT) produced by Gram-negative pathogenic bacteria can induce cell transformation, chromosomal abnormalities, and DNA damage. CDT induces replicative stress in human colorectal organoids, potentially contributing to carcinogenesis. Targeting CDT-carrying bacterial strains may be a promising therapeutic strategy for colorectal cancer patients.
The cytolethal distending toxin (CDT) is produced by several Gram-negative pathogenic bacteria. In addition to inflammation, experimental evidences are in favor of a protumoral role of CDT-harboring bacteria such as Escherichia coli, Campylobacter jejuni, or Helicobacter hepaticus. CDT may contribute to cell transformation in vitro and carcinogenesis in mice models, through the genotoxic action of CdtB catalytic subunit. Here, we investigate the mechanism of action by which CDT leads to genetic instability in human cell lines and colorectal organoids from healthy patients' biopsies. We demonstrate that CDT holotoxin induces a replicative stress dependent on CdtB. The slowing down of DNA replication occurs mainly in late S phase, resulting in the expression of fragile sites and important chromosomic aberrations. These DNA abnormalities induced after CDT treatment are responsible for anaphase bridge formation in mitosis and interphase DNA bridge between daughter cells in G1 phase. Moreover, CDT-genotoxic potential preferentially affects human cycling cells compared to quiescent cells. Finally, the toxin induces nuclear distension associated to DNA damage in proliferating cells of human colorectal organoids, resulting in decreased growth. Our findings thus identify CDT as a bacterial virulence factor targeting proliferating cells, such as human colorectal progenitors or stem cells, inducing replicative stress and genetic instability transmitted to daughter cells that may therefore contribute to carcinogenesis. As some CDT-carrying bacterial strains were detected in patients with colorectal cancer, targeting these bacteria could be a promising therapeutic strategy.
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