The nucleoside analog 5-aza-2'-deoxycytidine (5-aza-dC) is used to treat some hematopoietic malignancies. The mechanism of cell killing depends upon DNMT1, but is otherwise not clearly defined. Here we show that PARP1 forms covalent DNA adducts in human lymphoblast or fibroblasts treated with 5-aza-dC. Some adducts recovered from 5-aza-dC-treated cells have undergone cleavage by apoptotic caspases 3/7. Mapping of PARP1-DNA adducts, by a new method, "Adduct-Seq", demonstrates adduct enrichment at CpG-dense genomic locations that are targets of maintenance methylation by DNMT1. Covalent protein-DNA adducts can arrest replication and induce apoptosis, and these results raise the possibility that induction of PARP1-DNA adducts may contribute to cell killing in response to treatment with 5-aza-dC.

中文翻译：

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用5-氮杂-dC处理人细胞可诱导DNMT1靶向的基因组区域形成PARP1-DNA共价加合物

核苷类似物5-氮杂-2'-脱氧胞苷（5-氮杂-dC）用于治疗某些造血系统恶性肿瘤。细胞杀伤的机制取决于DNMT1，但没有明确定义。在这里，我们显示PARP1在经5-氮杂-dC处理的人淋巴母细胞或成纤维细胞中形成共价DNA加合物。从5-氮杂-dC处理的细胞中回收的一些加合物已被凋亡的胱天冬氨酸蛋白酶3/7裂解。通过新方法“加合物-Seq”绘制PARP1-DNA加合物的图谱显示，在DNMT1维持甲基化的目标的CpG密集基因组位置上，加合物富集。共价蛋白-DNA加合物可以阻止复制并诱导凋亡，并且这些结果增加了PARP1-DNA加合物的诱导可能响应于5-氮杂-dC处理而杀死细胞的可能性。