DNA ligase III mediates deoxynivalenol exposure-induced DNA damage in intestinal epithelial cells by regulating oxidative stress and interaction with PCNA.

Abstract

Deoxynivalenol (DON) is a widely distributed mycotoxin that is severely cytotoxic and genotoxic to animals and humans. The gut is the initial site of DON exposure and absorption, which can cause severe intestinal damage. However, the underlying mechanisms and effective therapeutic approaches remain unknown. Here, the study indicated that DON exposure caused significant DNA damage in intestinal porcine epithelial cells (IPEC-J2), enhanced significantly the expression of γ-H2AX and 8-hydroxy-2'-deoxyguanosine, and altered the mRNA expression of key genes in the DNA repair pathway. Among them, ligases3 (LIG3) is the key DNA damage/repair gene and the only ligase responsible for the replication and maintenance of mitochondrial DNA. The expression of LIG3 was significantly decreased after DON exposure and showed a dose-dependent effect, decreased expression of LIG3 exacerbates DON-induced cytotoxicity and genotoxicity, decreased cell viability, induced apoptosis and cell cycle arrest, activation of inflammatory factors and MAPK pathway. Furthermore, LIG3 directly binds and regulates PCNA and play a positive regulatory role in the cellular cytotoxicity and genotoxicity upon DON exposure. Collectively, the findings elucidate the regulatory function of LIG3 in DON-induced DNA damage, providing valuable insights into identifying molecular targets for the comprehensive prevention and control of DON contamination.