2'- C -cyano-2'-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes β-elimination that generates single-strand breaks with abnormal 3′-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 3′-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1−/− DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also identified BRCA1, FANCD2, and PCNA in the DNA repair pathways to CNDAC. Comparing CNDAC with the chemically related arabinosyl nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT), which both generate 3′-end blocking DNA lesions that are also repaired by TDP1, we found that inactivation of BRCA2 renders cells hypersensitive to CNDAC and CPT but not to AraC. By contrast, cells lacking PARP1 were only hypersensitive to CPT but not to CNDAC or AraC. Examination of TDP1 expression in the cancer cell line databases (CCLE, GDSC, NCI-60) and human cancers (TCGA) revealed a broad range of expression of TDP1 , which was correlated with PARP1 expression, TDP1 gene copy number and promoter methylation. Thus, this study identifies the importance of TDP1 as a novel determinant of response to CNDAC across various cancer types (especially non–small cell lung cancers), and demonstrates the differential involvement of BRCA2, PARP1, and TDP1 in the cellular responses to CNDAC, AraC, and CPT. Mol Cancer Ther; 16(11); 2543–51. ©2017 AACR .

中文翻译：

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TDP1对于修复由Sapacitabine诱导的DNA断裂至关重要，后者也是一种针对ATM和BRCA缺陷型肿瘤的核苷。

2'- C-氰基-2'-脱氧-1-β-d-阿拉伯糖基-戊呋喃糖基胞嘧啶（CNDAC）是抗癌药物萨帕他滨的活性代谢产物。CNDAC在DNA复制过程中被整合到基因组中，随后经过β消除，生成具有异常3'末端的单链断裂。由于酪氨酰DNA磷酸二酯酶1（TDP1）选择性水解非磷酸化的3'封闭末端，我们测试了其在修复CNDAC诱导的DNA损伤中的作用。我们显示缺少TDP1的细胞（禽类TDP1-/-DT40细胞和人TDP1 KO TSCER2和HCT116细胞）对CNDAC表现出明显的超敏性。我们还确定了CNCA的DNA修复途径中的BRCA1，FANCD2和PCNA。将CNDAC与化学相关的阿拉伯糖基核苷类似物，胞嘧啶阿拉伯糖苷（cytarabine，AraC）和拓扑异构酶I抑制剂喜树碱（CPT）进行比较，它们都产生3'端阻断性DNA损伤，这些损伤也被TDP1修复，我们发现BRCA2的失活使细胞对CNDAC和CPT而不是对AraC高度敏感。相比之下，缺少PARP1的细胞仅对CPT敏感，而对CNDAC或AraC不敏感。在癌细胞系数据库（CCLE，GDSC，NCI-60）和人类癌症（TCGA）中对TDP1表达的检查显示，TDP1的表达范围很广，这与PARP1表达，TDP1基因拷贝数和启动子甲基化有关。因此，这项研究确定了TDP1作为跨多种癌症类型（尤其是非小细胞肺癌）对CNDAC应答的新决定因素的重要性，并证明了BRCA2，PARP1和TDP1在对CNDAC的细胞应答中的不同参与， AraC和CPT。分子癌疗法；16（11）; 2543–51。©2017 AACR。