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Published on: May 15, 2021
DNA repair drives cisplatin-induced neuronal death
William J Nathan1, Chuanyuan Chen1, Rosy Sakr1
1Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Abstract:
Platinum agents are cornerstone therapies for many cancers but often cause neurotoxicity in post-mitotic tissues, for which effective interventions are lacking. This limitation reflects an incomplete understanding of neuronal responses to DNA damage. We show that nucleotide excision repair (NER) mediates cisplatin lesion removal in neurons; however, unlike its protective role in dividing cells, NER promotes neuronal death in response to cisplatin. This vulnerability arises because neurons possess low deoxynucleoside triphosphate (dNTP) pools. dNTPs are initially consumed during transcription-coupled NER to resolve transcription-blocking lesions. As dNTP levels become depleted, repair fails to complete, leading to accumulation of double-strand breaks, particularly during global-genome NER. Supplementation with deoxynucleosides or genetic upregulation of dNTP synthesis restores nucleotide pools, protects neurons from cell death, and reduces cisplatin-induced neuropathic pain. These findings identify limited dNTP availability as a key vulnerability in post-mitotic cells and suggest nucleoside supplementation as a potential strategy to mitigate chemotherapy-induced neurotoxicity.
Insights
Chemotherapy
Area of Science:
- Neuroscience
- Molecular Biology
- Oncology
Background:
- Platinum chemotherapy agents are vital for cancer treatment but cause significant neurotoxicity in non-dividing neurons.
- The mechanisms underlying this neuronal vulnerability to DNA damage remain poorly understood.
- Effective interventions for chemotherapy-induced neurotoxicity are currently lacking.
Purpose of the Study:
- To investigate the role of nucleotide excision repair (NER) in neuronal response to cisplatin.
- To identify the molecular mechanisms driving cisplatin-induced neurotoxicity in post-mitotic neurons.
- To explore potential therapeutic strategies for mitigating neurotoxicity.
Main Methods:
- Investigated cisplatin lesion removal via nucleotide excision repair (NER) in neurons.
- Assessed the impact of deoxynucleoside triphosphate (dNTP) pool levels on neuronal survival.
- Utilized deoxynucleoside supplementation and genetic upregulation of dNTP synthesis in experimental models.
Main Results:
- In neurons, NER promotes cell death in response to cisplatin, contrasting its protective role in dividing cells.
- Low deoxynucleoside triphosphate (dNTP) pools in neurons impair NER completion, leading to DNA double-strand breaks.
- Supplementation of deoxynucleosides or enhancement of dNTP synthesis protected neurons and reduced neuropathic pain.
Conclusions:
- Limited deoxynucleoside triphosphate (dNTP) availability is a critical vulnerability in post-mitotic neuronal cells exposed to DNA-damaging agents.
- Nucleoside supplementation emerges as a promising therapeutic strategy to prevent or reduce chemotherapy-induced neurotoxicity.
- Understanding neuronal DNA repair pathways is crucial for developing safer and more effective cancer treatments.
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