Mycoplasma DnaK expression increases cancer development in vivo upon DNA damage

• 成果类型: Article
• 署名作者: Benedetti, Francesca; Silvestri, Giovannino; Denaro, Frank; Finesso, Giovanni; Contreras-Galindo, Rafael; Munawwar, Arshi; Williams, Sumiko; Davis, Harry; Bryant, Joseph; Wang, Yin; Radaelli, Enrico; Rathinam, Chozha V.; Gallo, Robert C.; Zella, Davide
• 署名单位: University System of Maryland; University of Maryland Baltimore; University System of Maryland; University of Maryland Baltimore; University System of Maryland; University of Maryland Baltimore; University System of Maryland; University of Maryland Baltimore; Morgan State University; University of Pennsylvania; University of Alabama System; University of Alabama Birmingham; University System of Maryland; University of Maryland Baltimore
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12394
• DOI: 10.1073/pnas.2320859121
• 发表日期: 2024-03-01
• 关键词: colorectal-cancer; fusobacterium-nucleatum; tumor susceptibility; ethyl carbamate; gut microbiome; urethane; mice; carcinogenesis; association; induction

摘要

Well- controlled repair mechanisms are involved in the maintenance of genomic stability, and their failure can precipitate DNA abnormalities and elevate tumor risk. In addition, the tumor microenvironment, enriched with factors inducing oxidative stress and affecting cell cycle checkpoints, intensifies DNA damage when repair pathways falter. Recent research has unveiled associations between certain bacteria, including Mycoplasmas, and various cancers, and the causative mechanism(s) are under active investigation. We previously showed that Mycoplasma fermentans DnaK, an HSP70 family chaperone protein, hampers the activity of proteins like PARP1 and p53, crucial for genomic integrity. Moreover, our analysis of its interactome in human cancer cell lines revealed DnaK's engagement with several components of DNA- repair machinery. Finally, in vivo experiments performed in our laboratory using a DnaK knock - in mouse model generated by our group demonstrated that DnaK exposure led to increased DNA copy number variants, indicative of genomic instability. We present here evidence that expression of DnaK is linked to increased i) incidence of tumors in vivo upon exposure to urethane, a DNA damaging agent; ii) spontaneous DNA damage ex vivo; and iii) expression of proinflammatory cytokines ex vivo, variations in reactive oxygen species levels, and increased beta- galactosidase activity across tissues. Moreover, DnaK was associated with increased centromeric instability. Overall, these findings highlight the significance of Mycoplasma DnaK in the etiology of cancer and other genetic disorders providing a promising target for prevention, diagnostics, and therapeutics.