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Mechanism of cytarabine-induced neurotoxicity

  1. Author:
    Liu, Jia-Cheng
    Wang, Dongpeng [ORCID]
    Callen, Elsa
    Chen, Chuanyuan [ORCID]
    Noriega, Santiago [ORCID]
    Shang, Yafang
    Schürmann, David [ORCID]
    Song, Yawei
    Ramadoss, Gokul N [ORCID]
    Chari,Rajagopal [ORCID]
    Wong, Nancy
    Zhao, Yongge [ORCID]
    He, Yuan [ORCID]
    Aplan, Peter D [ORCID]
    Ward, Michael E [ORCID]
    Heintz, Nathaniel [ORCID]
    Rao, Anjana [ORCID]
    McKinnon, Peter J [ORCID]
    Caldecott, Keith W [ORCID]
    Schär, Primo [ORCID]
    Meng, Fei-Long [ORCID]
    Livak, Ferenc
    Wu, Wei [ORCID]
    Nussenzweig, André [ORCID]

  2. Author Address

    Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA., State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China., Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China., Department of Biomedicine, University of Basel, Basel, Switzerland., Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China., Gladstone Institutes, San Francisco, CA, USA., Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA., Department of Biology, Johns Hopkins University, Baltimore, MD, USA., Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA., National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA., Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA., La Jolla Institute for Immunology, La Jolla, CA, USA., Center for Pediatric Neurological Disease Research, St Jude Pediatric Translational Neuroscience Initiative, Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, TN, USA., Genome Damage and Stability Centre, University of Sussex, Brighton, UK., Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Academy of Natural Sciences (SANS), Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China., Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA. andre_nussenzweig@nih.gov.,
    1. Year: 2025
    2. Date: Jun 25
    3. Epub Date: 2025 06 25
  2. Journal: Nature
  4. Type of Article: Article
  1. 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. © 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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External Sources

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  2. DOI: 10.1038/s41586-025-09210-9
  3. PMID: 40562930
  4. PII : 10.1038/s41586-025-09210-9

Library Notes

  1. Fiscal Year: FY2024-2025
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