用 5-氮杂-2′-脱氧胞苷处理人细胞会在 DNMT1 靶向的基因组区域诱导形成 PARP1-DNA 共价加合物。
Treatment of human cells with 5-aza-dC induces formation of PARP1-DNA covalent adducts at genomic regions targeted by DNMT1.
机构信息
Department of Immunology, University of Washington, Seattle, WA, 98195, USA.
Department of Immunology, University of Washington, Seattle, WA, 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
出版信息
DNA Repair (Amst). 2020 Dec;96:102977. doi: 10.1016/j.dnarep.2020.102977. Epub 2020 Oct 2.
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.
核苷类似物 5-氮杂-2'-脱氧胞苷（5-aza-dC）被用于治疗某些血液系统恶性肿瘤。细胞杀伤的机制依赖于 DNMT1，但除此之外尚不清楚。在这里，我们表明 PARP1 在用人淋巴母细胞或成纤维细胞用 5-aza-dC 处理后会形成 DNA 加合物。从用 5-aza-dC 处理的细胞中回收的一些加合物已经被凋亡半胱天冬酶 3/7 切割。通过一种新的方法“Adduct-Seq”对 PARP1-DNA 加合物进行定位，证明加合物在 DNMT1 维持甲基化的 CpG 密集基因组位置富集。共价蛋白-DNA 加合物可以阻止复制并诱导细胞凋亡，这些结果提出了这样一种可能性，即 PARP1-DNA 加合物的诱导可能有助于对 5-aza-dC 治疗的细胞杀伤。
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