Circ_002363 is regulated by the RNA binding protein BCAS2 and inhibits neodymium oxide nanoparticle-induced DNA damage by non-homologous end-joining repair

Neodymium oxide nanoparticles (NPs-Nd2O3) are increasingly being used in industry and biomedicine, causing adverse health effects such as lung disease. However, the underlying molecular mechanisms controlling these adverse consequences are unknown at present. In this study, a human bronchial epithelial cell line (16HBE) was exposed to increasing concentrations of NPs-Nd2O3, and Sprague-Dawley rats were treated with NPs-Nd2O3 by intratracheal instillation. We found that NPs-Nd2O3 exposure induced DNA damage and down-regulated levels of circular RNA (circRNA) circ_002363 in 16HBE cells as well as in rat lung tissue. We also observed that circ_002363 levels in the serum of workers employed in the production of NPs-Nd2O3 diminished as thework time progressed, suggesting that circ_002363 may be a potential biomarker of lung injury. Functional experiments showed that circ_002363 significantly inhibited DNA damage induced by NPs-Nd2O3. RNA pull-down and western blot assays found that circ_002363 interacted with proteins PARP1/ Ku70/Ku80/Rad50, which are critical participants in non-homologous end-joining (NHEJ) DNA repair. Moreover, we found that formation of circ_002363 was regulated by the RNA binding protein Breast Carcinoma Amplified Sequence 2 (BCAS2). The BCAS2 protein affected circ_002363 expression through interaction with Pre-DNA2, the host gene of circ_002363, in NPs-Nd2O3-exposed 16HBE cells. In conclusion, our findings show first that circ_002363, which is regulated by BCAS2, acts as regulator of DNA damage via the NHEJ pathway. These results enhance our understanding of the regulatory mechanisms controlling the actions of circular RNAs and highlight the relationship between genetics and epigenetics in the development of diseases following exposure to environmental chemicals.

Automated summary

In this study, NPs-Nd2O3 exposure was found to induce DNA damage and down-regulate circ_002363 levels in human bronchial epithelial cells and rat lung tissue. Functional experiments demonstrated that circ_002363 acts as a regulator of DNA damage by interacting with proteins involved in the NHEJ DNA repair pathway. The formation of circ_002363 was found to be regulated by the RNA binding protein BCAS2. These findings provide new insights into the regulatory mechanisms of circular RNAs and the relationship between genetics and epigenetics in the development of diseases following exposure to environmental chemicals.