近日，美国国家癌症研究所教授André Nussenzweig及其课题组研究出阿糖胞苷诱导神经毒性的机制。该研究于2025年6月25日发表于国际一流学术期刊《自然》杂志上。

在这里，课题组发现一些胞苷类似物，如阿糖胞苷，在TET介导的活性5-甲基胞嘧啶去甲基化过程中，通过中断TDG依赖的碱基切除修复，腺苷DNA双链断裂。这些双链断裂经常被DNA连接酶转化为缺失和易位。在体内，小脑中的浦肯野细胞和高尔基细胞是仅有的由于阿糖胞苷而表现出高水平DNA损伤的神经元群。在浦肯野细胞中，TET靶向以增强子相关组蛋白修饰为标志的高表达基因体。这些基因中有许多控制运动协调，这就解释了长期以来公认的阿糖胞苷对小脑神经的毒性。课题组发现其他胞苷类似物，如吉西他滨，在神经元中只引起单链断裂，通过DNA连接酶修复。毒性最小。他们的发现揭示了TET介导的DNA去甲基化、碱基切除修复和神经元基因表达之间的机制联系。这些结果也为一类重要的抗肿瘤药物的不同神经毒性提供了合理的解释。

据了解，有丝分裂后神经元具有高水平的甲基化胞嘧啶及其氧化中间体，如5-羟甲基胞嘧啶。然而，这些DNA表观遗传修饰的功能相关性尚不清楚。

附：英文原文

Title: Mechanism of cytarabine-induced neurotoxicity

Author: Liu, Jia-Cheng, Wang, Dongpeng, Callen, Elsa, Chen, Chuanyuan, Noriega, Santiago, Shang, Yafang, Schrmann, 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., Schr, Primo, Meng, Fei-Long, Livak, Ferenc, Wu, Wei, Nussenzweig, Andr

Issue&Volume: 2025-06-25

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 ligase4. 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 ligase3 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.

DOI: 10.1038/s41586-025-09210-9

Source: https://www.nature.com/articles/s41586-025-09210-9