Cisplatin-induced DNA crosslinks trigger neurotoxicity in C. elegans

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Cisplatin (CisPt) is an anticancer drug that can cause neurotoxicity, affecting both post-mitotic and replicating cells.
• The precise DNA lesions induced by CisPt and their contribution to neurotoxicity remain incompletely understood.

Purpose of the Study:

• To investigate the role of specific DNA repair pathways in mitigating cisplatin-induced neurotoxicity.
• To elucidate the relevance of different CisPt-induced DNA lesions in evoking neurotoxicity.

Main Methods:

• Comparative analysis of wild-type and DNA repair-deficient C. elegans mutants.
• Assessment of neurotoxicity using post-mitotic chemosensory neuron functionality (AWA neurons).
• Analysis of gene expression changes and germline apoptosis following CisPt treatment.

Main Results:

• Deficiency in ERCC-1, crucial for nucleotide excision repair (NER) and interstrand crosslink (ICL) repair, most significantly enhanced CisPt neurotoxicity in AWA neurons without causing cell death.
• Mutants deficient in XPF-1, CSB-1, CSB-1;XPC-1, and MSH-6 showed increased sensitivity to CisPt neurotoxicity.
• Specific DNA repair pathways, including ERCC1/XPF, CSB, and MSH6, appear critical in protecting against chemotherapy-induced neuropathy.

Conclusions:

• Cisplatin-induced neurotoxicity, including sensory neuropathy, is mediated by DNA intra- and interstrand crosslinks that are substrates for NER and ICL repair.
• Efficient DNA repair mechanisms, particularly those involving ERCC1/XPF, CSB, and MSH6, are essential for preventing cisplatin-induced neurotoxicity during anticancer therapy.