Differential DNA damage response and cell fate in human lung cells after exposure to genotoxic compounds

• Published in: Toxicology in vitro 2024-02, Vol.94, p.105710-105710, Article 105710
• Main Authors: Libalova, H., Zavodna, T., Margaryan, H., Elzeinova, F., Milcova, A., Vrbova, K., Barosova, H., Cervena, T., Topinka, J., Rössner, P.
• Format: Article
• Language: English
• Subjects: Anticancer drugs; Cell fate; DNA damage response; Genotoxicity; Polycyclic aromatic hydrocarbons
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2023.105710

DNA damage can impair normal cellular functions and result in various pathophysiological processes including cardiovascular diseases and cancer. We compared the genotoxic potential of diverse DNA damaging agents, and focused on their effects on the DNA damage response (DDR) and cell fate in human lung cells BEAS-2B. Polycyclic aromatic hydrocarbons [PAHs; benzo[a]pyrene (B[a]P), 1-nitropyrene (1-NP)] induced DNA strand breaks and oxidative damage to DNA; anticancer drugs doxorubicin (DOX) and 5-bromo-2′-deoxyuridine (BrdU) were less effective. DOX triggered the most robust p53 signaling indicating activation of DDR, followed by cell cycle arrest in the G2/M phase, induction of apoptosis and senescence, possibly due to the severe and irreparable DNA lesions. BrdU not only activated p53, but also increased the percentage of G1-phased cells and caused a massive accumulation of senescent cells. In contrast, regardless the activation of p53, both PAHs did not substantially affect the cell cycle distribution or senescence. Finally, a small fraction of cells accumulated only in the G2/M phase and exhibited increased cell death after the prolonged incubation with B[a]P. Overall, we characterized differential responses to diverse DNA damaging agents resulting in specific cell fate and highlighted the key role of DNA lesion type and the p53 signaling persistence. •PAHs induced considerably higher level of DNA damage than DOX and BrdU.•DOX treatment was more toxic and led to G2 arrest, senescence and apoptosis.•BrdU triggered senescence possibly due to an alternative mechanism.•Despite slight increase of apoptosis, PAHs displayed better survival of cells.