Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel
Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel
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DOI：
10.1016/j.dnarep.2013.09.001
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发表时间：
2014-01-01
期刊：
影响因子：
3.8
通讯作者：
Pommier, Yves
中科院分区：
文献类型：
--
作者：
Gao, Rui;Das, Benu Brata;Pommier, Yves
酪氨酰-DNA-磷酸二酯酶1（TDP 1）通过催化水解捕获的拓扑异构酶I（Top1）切割复合物（Top1 cc）的酪氨酰-DNA-磷酸二酯键来修复3 '阻断DNA损伤。它还去除了来自氧化损伤或链终止抗癌和抗病毒核苷掺入的3 '-阻断残基。因此，TDP 1被认为是对Top1抑制剂和链终止核苷的抗性以及可能的基因组稳定性的决定因素。在NCI发育治疗性抗癌筛选（NCI-60）的60个细胞系中，其全基因组转录组和突变最近已被表征，我们发现了两个TDP 1缺陷的人肺癌细胞系（NCI_H522和HOP_62）。HOP_62显示不可检测的TDP 1 mRNA，NCI_H522在高度保守的氨基酸残基（K292 E）处携带TDP 1的纯合有害突变。在来自两种细胞系的细胞裂解物中证明了TDP 1蛋白的缺失和TDP 1催化活性的缺乏。在HOP_62中缺乏TDP 1表达被证明是由于TDP 1启动子高甲基化。我们的研究提供了对TDP 1在癌症中可能失活及其与Top1靶向药物的细胞反应的关系的见解。它还揭示了两个TDP 1敲除肺癌细胞系，用于进一步的TDP 1功能分析。由爱思唯尔公司出版
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) repairs 3'-blocking DNA lesions by catalytically hydrolyzing the tyrosyl-DNA-phosphodiester bond of trapped topoisomerase I (Top1) cleavage complexes (Topl cc). It also removes 3'-blocking residues derived from oxidative damage or incorporation of chain terminating anticancer and antiviral nucleosides. Thus, TDP1 is regarded as a determinant of resistance to Top1 inhibitors and chain terminating nucleosides, and possibly of genomic stability. In the 60 cell lines of the NCI Developmental Therapeutic Anticancer Screen (the NCI-60), whose whole genome transcriptome and mutations have recently been characterized, we discovered two human lung cancer cell lines deficient for TDP1 (NCI_H522 and HOP_62). HOP_62 shows undetectable TDP1 mRNA and NCI_H522 bears a homozygous deleterious mutation of TDP1 at a highly conserved amino acid residue (K292E). Absence of TDP1 protein and lack of TDP1 catalytic activity were demonstrated in cell lysates from both cell lines. Lack of TDP1 expression in HOP_62 was shown to be due to TDP1 promoter hypermethylation. Our study provides insights into the possible inactivation of TDP1 in cancers and its relationship to cellular response to Top1-targeted drugs. It also reveals two TDP1 knockout lung cancer cell lines for further TDP1 functional analyses. Published by Elsevier B.V.