DNA repair drives cisplatin-induced neuronal death [RNA-Seq]

Cisplatin and similar-acting alkylating chemotherapy agents are the cornerstone treatments for many types of cancers. While effective, these drugs induce long-term side-effects in post-mitotic tissues including the nervous system. There are no known effective pharmacological interventions for chemotherapy-induced neurotoxicity, in part due to our limited understanding of how neurons and other non-dividing cells respond to DNA damage. Here, we show that nucleotide excision repair (NER) is responsible for cisplatin adduct removal in human neurons. However, contrary to its protective role in dividing cells, NER drives neuronal cell death in response to cisplatin. Through excision repair synthesis, NER exhausts low levels of deoxynucleoside triphosphate (dNTP) pools found in post-mitotic neurons. dNTP pools are first consumed to resolve transcription-blocking lesions through transcription-coupled NER. When dNTPs become exhausted, toxic double-strand breaks accumulate across the genome primarily because of incomplete global-genome NER. Supplementation with deoxynucleosides through pharmacological or genetic means protects neurons from cisplatin-induced cell death and reduces cisplatin-induced neuropathic pain in mice. These results identify low levels of endogenous dNTP pools as a vulnerability of post-mitotic cells to DNA damage and suggest nucleoside supplementation as a strategy to protect patients from chemotherapy-induced neurotoxicity.