XRCC4, which is inhibited by PFDA, regulates DNA damage repair and cell chemosensitivity

Area of Science:

• Environmental toxicology
• Molecular oncology
• Genetics

Background:

• Environmental pollution is linked to increased gastric cancer incidence and treatment challenges.
• Persistent pollutants like perfluorodecanoic acid (PFDA) are widespread environmental contaminants.
• The precise mechanisms by which environmental factors influence cancer genotoxicity and treatment remain incompletely understood.

Purpose of the Study:

• To investigate the genotoxic effects of PFDA on gastric cells and its impact on DNA repair pathways.
• To determine how PFDA exposure affects cellular sensitivity to chemotherapy.
• To elucidate the molecular mechanisms underlying PFDA-induced alterations in DNA repair and cell survival.

Main Methods:

• Treatment of human and mouse gastric cell lines and mice with PFDA.
• Analysis of DNA double-strand breaks (DSBs) using γ-H2AX immunoblot and PCR.
• Gene expression profiling using microarray analysis.
• Investigation of the role of XRCC4 and p53 in PFDA's effects.
• Assessment of cellular sensitivity to chemotherapy.

Main Results:

• PFDA exposure induced DNA double-strand breaks (DSBs) in gastric cells.
• PFDA significantly altered cellular sensitivity to chemotherapy agents.
• PFDA altered the expression of key DNA repair genes, notably inhibiting the DNA repair protein XRCC4.
• PFDA-induced p53 inhibition rescued cells from apoptosis triggered by nonhomologous end-joining (NHEJ) inactivation.
• T-cell specific factor 4 was identified as a potential upstream regulator of XRCC4.

Conclusions:

• Perfluorinated chemicals like PFDA can promote DNA damage and affect chemotherapeutic sensitivity in gastric cancer.
• PFDA interferes with the NHEJ DNA repair pathway, mediated by XRCC4 inhibition.
• PFDA-induced p53 reduction plays a critical role in cell survival by mitigating apoptosis associated with DNA repair pathway disruption.