TDP1 deficiency sensitizes human cells to base damage via distinct topoisomerase I and PARP mechanisms with potential applications for cancer therapy.
TDP1 deficiency sensitizes human cells to base damage via distinct topoisomerase I and PARP mechanisms with potential applications for cancer therapy.
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DOI：
10.1093/nar/gkt1260
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发表时间：
2014-03
影响因子：
14.9
通讯作者：
El-Khamisy SF
中科院分区：
文献类型：
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作者：
Alagoz M;Wells OS;El-Khamisy SF
碱基损伤和拓扑异构酶I（Top1）连接的DNA断裂是内源性DNA断裂的丰富形式，有助于遗传性共济失调和广泛的抗癌药物的细胞毒性的基础。尽管它们的频率，修复这些形式的DNA断裂的重叠机制在很大程度上是未知的。在这里，我们报告说，酪氨酰DNA磷酸二酯酶1（TDP 1）的消耗敏感的人类细胞烷基化损伤和脱嘌呤/脱嘧啶核酸内切酶I（APE 1）的额外消耗赋予超敏反应以上的TDP 1或APE 1单独消耗观察。DNA断裂的定量和克隆形成存活测定证实了TDP 1对碱基损伤的反应，独立于APE 1。对烷基化损伤的超敏反应通过Top1的耗尽而部分恢复，这说明烷基化剂可以触发细胞毒性Top1-断裂。虽然PARP活性的抑制不会使TDP 1缺陷细胞对Top1毒物敏感，但它赋予对烷基化损伤的敏感性增加，突出了PARP和TDP 1在响应遗传毒性挑战中的部分重叠作用。最后，我们证明，其中TDP 1是固有缺陷的癌细胞是对烷基化损伤过敏和TDP 1耗尽敏感的胶质母细胞瘤耐药癌细胞的烷化剂替莫唑胺。
Base damage and topoisomerase I (Top1)-linked DNA breaks are abundant forms of endogenous DNA breakage, contributing to hereditary ataxia and underlying the cytotoxicity of a wide range of anti-cancer agents. Despite their frequency, the overlapping mechanisms that repair these forms of DNA breakage are largely unknown. Here, we report that depletion of Tyrosyl DNA phosphodiesterase 1 (TDP1) sensitizes human cells to alkylation damage and the additional depletion of apurinic/apyrimidinic endonuclease I (APE1) confers hypersensitivity above that observed for TDP1 or APE1 depletion alone. Quantification of DNA breaks and clonogenic survival assays confirm a role for TDP1 in response to base damage, independently of APE1. The hypersensitivity to alkylation damage is partly restored by depletion of Top1, illustrating that alkylating agents can trigger cytotoxic Top1-breaks. Although inhibition of PARP activity does not sensitize TDP1-deficient cells to Top1 poisons, it confers increased sensitivity to alkylation damage, highlighting partially overlapping roles for PARP and TDP1 in response to genotoxic challenge. Finally, we demonstrate that cancer cells in which TDP1 is inherently deficient are hypersensitive to alkylation damage and that TDP1 depletion sensitizes glioblastoma-resistant cancer cells to the alkylating agent temozolomide.
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分离DNA碱基切除修复的小分子抑制剂。
影响因子：
14.9
作者：
Madhusudan, S;Smart, F;Shrimpton, P;Parsons, JL;Gardiner, L;Houlbrook, S;Talbot, DC;Hammonds, T;Freemont, PA;Sternberg, MJE;Dianov, GL;Hickson, ID
通讯作者：
Hickson, ID
影响因子：
4.8
作者：
Interthal, H;Chen, HJ;Champoux, JJ
通讯作者：
Champoux, JJ
影响因子：
3.8
作者：
Demple, B;Sung, JS
通讯作者：
Sung, JS
影响因子：
4.3
作者：
Chiang, Shih-Chieh;Carroll, Jean;El-Khamisy, Sherif F.
通讯作者：
El-Khamisy, Sherif F.
DOI：
10.1038/nrc3185
发表时间：
2012-01-12
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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