TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs.
TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs.
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DOI：
10.1093/nar/gkt483
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发表时间：
2013-09
影响因子：
14.9
通讯作者：
Pommier Y
中科院分区：
文献类型：
--
作者：
Huang SY;Murai J;Dalla Rosa I;Dexheimer TS;Naumova A;Gmeiner WH;Pommier Y
链终止核苷类似物（CTNAs）引起DNA复制叉的延迟或过早终止，被广泛用作抗癌和抗病毒药物。然而，细胞如何修复这些药物引起的DNA损伤还不是很清楚。在这里，我们揭示了酪氨酸- DNA磷酸二酯酶1 （TDP1）在修复由CTNAs诱导的核和线粒体DNA损伤中的重要性。在研究四种ctna -阿昔洛韦（ACV）、阿糖胞苷（阿拉- c）、齐多夫定（AZT）和扎西他滨（ddC）的作用时，我们发现TDP1能够从DNA 3 '端去除共价连接的相应ctna。我们还发现，当ACV和Ara-C处理Tdp1−/−细胞时，Tdp1−/−细胞是超敏感的，并且积累了更多的DNA损伤，这表明Tdp1参与修复cna诱导的DNA损伤。由于已知AZT和ddC会导致线粒体功能障碍，我们检测了TDP1是否修复了它们诱导的线粒体DNA损伤。我们发现AZT和ddC处理导致Tdp1−/−细胞中线粒体DNA的更大损耗。因此，TDP1似乎对修复由ctna引起的核和线粒体DNA损伤至关重要。
Chain-terminating nucleoside analogs (CTNAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these drugs. Here, we reveal the importance of tyrosyl–DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by CTNAs. On investigating the effects of four CTNAs—acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC)—we show that TDP1 is capable of removing the covalently linked corresponding CTNAs from DNA 3′-ends. We also show that Tdp1−/− cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing CTNA-induced DNA damage. As AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We find that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1−/− cells. Thus, TDP1 seems to be critical for repairing nuclear and mitochondrial DNA damage caused by CTNAs.
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影响因子：
3.7
作者：
Fu X;Wan S;Lyu YL;Liu LF;Qi H
通讯作者：
Qi H
影响因子：
4.8
作者：
Interthal, H;Chen, HJ;Champoux, JJ
通讯作者：
Champoux, JJ
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Das, Benu Brata;Antony, Smitha;Pommier, Yves
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Pommier, Yves
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Hirano, Ryuki;Interthal, Heidrun;Boerkoel, Cornelius F.
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Boerkoel, Cornelius F.
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作者：
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