Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2(S) short isoform

Huang Shar-yin N.; Dalla Rosa Ilaria; Michaels Stephanie A.; Tulumello David V.; Agama Keli; Khiati Salim; Jean Sae Rin; Baechler Simone A.; Factor Valentina M.; Varma Sudhir; Murai Junko; Jenkins Lisa M. Miller; Kelley Shana O.; Pommier Yves

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Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2(S) short isoform

机译：线粒体酪氨酸-DNA磷酸二酯酶2及其TDP2短同种型

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Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs abortive topoisomerase II cleavage complexes. Here, we identify a novel short isoform of TDP2 (TDP2(S)) expressed from an alternative transcription start site. TDP2(S) contains a mitochondrial targeting sequence, contributing to its enrichment in the mitochondria and cytosol, while full-length TDP2 contains a nuclear localization signal and the ubiquitin-associated domain in the N-terminus. Our study reveals that both TDP2 isoforms are present and active in the mitochondria. Comparison of isogenic wild-type (WT) and TDP2 knockout (TDP2(-/-/-)) DT40 cells shows that TDP2(-/-/-) cells are hypersensitive to mitochondrial-targeted doxorubicin (mtDox), and that complementing TDP2(-/-/-) cells with human TDP2 restores resistance to mtDox. Furthermore, mtDox selectively depletes mitochondrial DNA in TDP2(-/-/-) cells. Using CRISPR-engineered human cells expressing only the TDP2(S) isoform, we show that TDP2(S) also protects human cells against mtDox. Finally, lack of TDP2 in the mitochondria reduces the mitochondria transcription levels in two different human cell lines. In addition to identifying a novel TDP2(S) isoform, our report demonstrates the presence and importance of both TDP2 isoforms in the mitochondria.

机译：酪氨酸-DNA磷酸二酯酶2（TDP2）修理流产拓扑异构酶II切割复合物。这里，我们鉴定了从替代转录开始站点表达的TDP2（TDP2）的新型短同种型。 TDP2含有线粒体靶向序列，有助于其在线粒体和细胞溶胶中的富集，而全长TDP2含有N-末端中的核定位信号和泛素相关结构域。我们的研究表明，在线粒体中存在TDP2同种型并活跃。上源性野生型（WT）和TDP2敲除的比较（TDP2（ - / - / - ））DT40细胞表明TDP2（ - / - / - ）细胞对线粒体靶向的多柔比星（MTDOX）过敏，并补充TDP2 （ - / - ）具有人TDP2的细胞恢复对MTDOX的抗性。此外，MTDOX在TDP2（ - / - / - ）细胞中选择性地耗尽线粒体DNA。使用仅表达TDP2同种型的CRISPR工程化人体细胞，我们表明TDP2也保护人体细胞对抗MTDOX。最后，线粒体中缺乏TDP2减少了两种不同人细胞系中的线粒体转录水平。除了鉴定新型TDP2同种型外，我们的报告还证明了TDP2同种型在线粒体中的存在和重要性。

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来源
《EMBO reports》 |2018年第3期|共14页
作者
Huang Shar-yin N.; Dalla Rosa Ilaria; Michaels Stephanie A.; Tulumello David V.; Agama Keli; Khiati Salim; Jean Sae Rin; Baechler Simone A.; Factor Valentina M.; Varma Sudhir; Murai Junko; Jenkins Lisa M. Miller; Kelley Shana O.; Pommier Yves;
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NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

Univ Toronto Dept Biochem Fac Med Toronto ON Canada;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

Univ Toronto Dept Biochem Fac Med Toronto ON Canada;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

NCI Cell Biol Lab Ctr Canc Res NIH Bethesda MD 20892 USA;

Univ Toronto Dept Biochem Fac Med Toronto ON Canada;

NCI Mol Pharmacol Lab Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

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原文格式 PDF
正文语种 eng
中图分类分子生物学;
关键词
DNA repair; mitochondria; mitochondrial DNA; topoisomerase;

机译：DNA修复;线粒体;线粒体DNA;拓扑异构酶;

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专利

1. Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2(S) short isoform [J] . Huang Shar-yin N., Dalla Rosa Ilaria, Michaels Stephanie A., EMBO reports . 2018,第3期

机译：线粒体酪氨酸-DNA磷酸二酯酶2及其TDP2短同种型
2. Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2) [J] . Yu Le-Mao, Hu Zhu, Chen Yu, European Journal of Medicinal Chemistry: Chimie Therapeutique . 2018,第期

机译：呋喹啉代亚磷酸酯酶抑制剂的合成及结构 - 活性关系（TDP2）
3. New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2) [J] . Ribeiro Carlos J. A., Kankanala Jayakanth, Shi Ke, European journal of pharmaceutical sciences . 2018,第期

机译：用于酪氨酸 - DNA磷酸二酯酶2的小分子抑制剂的新型荧光高通量筛选测定（TDP2）
4. Theragnosis with PDT and IgM Antibody Anti Isoform 4 SOD Mitochondrial Labeled with PpIX in SiHa, MDA-MB-231 and CaCo-2 Cell Lines [C] . Claudia Martinez Garcia, Yolanda Medina Flores, José Manuel de la Rosa Vázquez, Mexican Symposium on Medical Physics . 2019

机译：具有PDT和IgM抗体抗同种型4 SOD线粒体用PPIX，MDA-MB-231和CACO-2细胞系标记的SOD线粒体
5. Computational and combinatorial design of protein-based inhibitors of human tyrosyl-DNA phosphodiesterase. [D] . Stemm, Mina Catherine. 2005

机译：基于蛋白质的人酪氨酰-DNA磷酸二酯酶抑制剂的计算和组合设计。
6. Mitochondrial tyrosyl‐DNA phosphodiesterase 2 and its TDP2S short isoform [O] . Shar‐yin N Huang, Ilaria Dalla Rosa, Stephanie A Michaels, 2018

机译：线粒体酪氨酰-DNA磷酸二酯酶2及其TDP2S短异构体
7. New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2) [O] . Carlos J.A. Ribeiro, Jayakanth Kankanala, Ke Shi, 2018

机译：用于酪氨酸-DNA磷酸二氧磷酸酯酶2的小分子抑制剂的新型荧光高通量筛选测定（TDP2）

Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2(S) short isoform

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