DNA repair drives cisplatin-induced neuronal death

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 neurotoxicities, 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 DNA 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.