Mechanism of cytarabine-induced neurotoxicity
成果类型：
Article
署名作者：
Liu, Jia-Cheng; Wang, Dongpeng; Callen, Elsa; Chen, Chuanyuan; Noriega, Santiago; Shang, Yafang; Schurmann, David; Song, Yawei; Ramadoss, Gokul N.; Chari, Raj; Wong, Nancy; Zhao, Yongge; He, Yuan; Aplan, Peter D.; Ward, Michael E.; Heintz, Nathaniel; Rao, Anjana; McKinnon, Peter J.; Caldecott, Keith W.; Schar, Primo; Meng, Fei-Long; Livak, Ferenc; Wu, Wei; Nussenzweig, Andre
署名单位：
National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; University of Basel; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; University of Chinese Academy of Sciences, CAS; University of California System; University of California San Francisco; The J David Gladstone Institutes; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Johns Hopkins University; Johns Hopkins University; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS); Rockefeller University; Howard Hughes Medical Institute; La Jolla Institute for Immunology; St Jude Children's Research Hospital; University of Sussex; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Center for Excellence in Molecular Cell Science, CAS; Chinese Academy of Sciences; Institute of Biophysics, CAS
刊物名称：
Nature
ISSN/ISSBN：
0028-2724
DOI：
10.1038/s41586-025-09210-9
发表日期：
2025-07-31
关键词：
genome-wide
dna demethylation
breaks
transcription
methylation
enrichment
neurons
repair
roles
摘要：
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.