Mycoplasma DnaK expression increases cancer development in vivo upon DNA damage

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-03, Vol.121 (10), p.e2320859121
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Abnormalities; Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biological Sciences; Cancer; Cell cycle; Copy number; Damage; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; DnaK protein; Escherichia coli Proteins - metabolism; Galactosidase; Gene expression; Genetic disorders; Genomic instability; Genomics; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Inflammation; Mice; Mycoplasma; Mycoplasma - genetics; Neoplasms - genetics; Oxidative stress; p53 Protein; Poly(ADP-ribose) polymerase; Proteins; Reactive oxygen species; Repair; Tumor cell lines; Tumor Microenvironment; Tumors; β-Galactosidase
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2320859121

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 , and various cancers, and the causative mechanism(s) are under active investigation. We previously showed that 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 β-galactosidase activity across tissues. Moreover, DnaK was associated with increased centromeric instability. Overall, these findings highlight the significance of DnaK in the etiology of cancer and other genetic disorders providing a promising target for prevention, diagnostics, and therapeutics.