Mechanism of cytarabine-induced neurotoxicity

Jia-Cheng Liu, Dongpeng Wang, Elsa Callen, Chuanyuan Chen, Santiago Noriega, Yafang Shang, David Schürmann, Yawei Song, Gokul N. Ramadoss, Raj Chari, Nancy Wong, Yongge Zhao, Yuan He, Peter D. Aplan, Michael E. Ward, Nathaniel Heintz, Anjana Rao, Peter J. McKinnon, Keith W. Caldecott, Primo Schär, Fei-Long Meng, Ferenc Livak, Wei Wu and André Nussenzweig ()
Additional contact information
Jia-Cheng Liu: NIH
Dongpeng Wang: NIH
Elsa Callen: NIH
Chuanyuan Chen: NIH
Santiago Noriega: NIH
Yafang Shang: University of Chinese Academy of Sciences
David Schürmann: University of Basel
Yawei Song: University of Chinese Academy of Sciences
Gokul N. Ramadoss: Gladstone Institutes
Raj Chari: Frederick National Laboratory for Cancer Research
Nancy Wong: NIH
Yongge Zhao: NIH
Yuan He: Johns Hopkins University
Peter D. Aplan: NIH
Michael E. Ward: NIH
Nathaniel Heintz: The Rockefeller University
Anjana Rao: La Jolla Institute for Immunology
Peter J. McKinnon: St Jude Children’s Research Hospital
Keith W. Caldecott: University of Sussex
Primo Schär: University of Basel
Fei-Long Meng: University of Chinese Academy of Sciences
Ferenc Livak: NIH
Wei Wu: University of Chinese Academy of Sciences
André Nussenzweig: NIH

Nature, 2025, vol. 643, issue 8074, 1400-1409

Abstract: Abstract Postmitotic neurons have high levels of methylated cytosine and its oxidized intermediates such as 5-hydroxymethylcytosine1. However, the functional relevance of these epigenetic modifications of DNA are poorly understood. Here we show that some cytidine analogues, such as cytarabine, cause DNA double-strand breaks during TET-mediated active 5-methylcytosine demethylation by interrupting TDG-dependent base excision repair. These double-strand breaks are frequently converted into deletions and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage due to cytarabine. In Purkinje cells, TET targets highly expressed gene bodies marked by enhancer-associated histone modifications. Many of these genes control movement coordination, which explains the long-recognized cerebellar neurotoxicity of cytarabine2. We show that other cytidine analogues, such as gemcitabine, cause only single-strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons. The results also provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.

Date: 2025
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DOI: 10.1038/s41586-025-09210-9

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