Limited Deoxynucleoside Pools Underlie Cisplatin-Induced Neurotoxicity

Platinum-based chemotherapies such as cisplatin are first-line treatments for many solid tumors, yet they frequently cause debilitating peripheral neuropathy in post-mitotic neurons. The molecular basis of this selective vulnerability has remained poorly understood, and no effective preventive interventions currently exist. In a recent study, Nathan and colleagues uncovered a counterintuitive mechanism: The same DNA repair process that protects dividing cells from cisplatin-induced damage paradoxically kills neurons that attempt the same repairs. The authors found that neurons engage nucleotide excision repair (NER) to remove cisplatin–DNA adducts, activating both the transcription-coupled and global-genome (GG) subpathways of NER. Unlike in proliferating cells, however, neurons maintain only modest pools of deoxynucleoside triphosphates (dNTP) required to fill in gaps left by excision repair. TC-NER initially consumes these limited dNTP reserves to resolve transcription-blocking lesions on active genes. As dNTP levels become exhausted, GG-NER can no longer complete repairs genome-wide, causing incomplete excision events to collapse into toxic DNA double-strand breaks (DSB). This demonstrated vulnerability could be pharmacologically targeted, as supplementing neurons with exogenous deoxynucleosides significantly improved neuronal survival following cisplatin exposure. Genetic strategies that upregulated dNTP biosynthesis produced comparable protection. Translating these findings to a mouse model of cisplatin-induced neuropathy, nucleoside supplementation reduced neuropathic pain behavior, suggesting clinical utility. These findings reframe chemotherapy-induced peripheral neuropathy as a consequence of aberrant DNA repair rather than direct DNA damage and identify dNTP insufficiency as a targetable metabolic bottleneck unique to post-mitotic cells. Therefore, nucleoside supplementation may be a potential clinical strategy to selectively shield neurons during platinum-based chemotherapy without compromising antitumor efficacy.Nathan WJ, Chen C, Sakr R, Mietto BS, van Batenburg V, van den Berg J, et al. DNA repair drives cisplatin-induced neuronal death. Cell 2026;189:4005–21.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.