更新于：2024-11-01

TDP1

更新于：2024-11-01

基本信息

别名

FLJ11090、SCAN1、TDP1

+ [2]

简介

DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate.

关联

项与 TDP1 相关的药物

NSC-88915

靶点

TDP1

作用机制

TDP1 inhibitors

在研机构

National Cancer Institute

原研机构

National Cancer Institute

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TDP1 相关的临床结果

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100 项与 TDP1 相关的转化医学

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0 项与 TDP1 相关的专利（医药）

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386

项与 TDP1 相关的文献（医药）

2024-11-01·IUBMB Life

Apurinic/apyrimidinic endonuclease 1 has major impact in prevention of suicidal covalent DNA–protein crosslink with apurinic/apyrimidinic site in cellular extracts

Article

作者: Lavrik, Olga I. ; Rechkunova, Nadejda I. ; Dyrkheeva, Nadezhda S. ; Lebedeva, Natalia A.

AbstractDNA–protein crosslinks (DPC) are common DNA lesions induced by various external and endogenous agents. One of the sources of DPC is the apurinic/apyrimidinic site (AP site) and proteins interacting with it. Some proteins possessing AP lyase activity form covalent complexes with AP site‐containing DNA without borohydride reduction (suicidal crosslinks). We have shown earlier that tyrosyl‐DNA phosphodiesterase 1 (TDP1) but not AP endonuclease 1 (APE1) is able to remove intact OGG1 from protein–DNA adducts, whereas APE1 is able to prevent the formation of DPC by hydrolyzing the AP site. Here we demonstrate that TDP1 can remove intact PARP2 but not XRCC1 from covalent enzyme–DNA adducts with AP‐DNA formed in the absence of APE1. We also analyzed an impact of APE1 and TDP1 on the efficiency of DPC formation in APE1−/− or TDP1−/− cell extracts. Our data revealed that APE1 depletion leads to increased levels of PARP1–DNA crosslinks, whereas TDP1 deficiency has little effect on DPC formation.

2024-10-01·DNA Repair

Exploring the removal of Spo11 and topoisomerases from DNA breaks in S. cerevisiae by human Tyrosyl DNA Phosphodiesterase 2

Article

作者: Allison, Rachal M. ; Cejka, Petr ; Cannavo, Elda ; Neale, Matthew J. ; Harper, Jon A ; Neale, Matthew J ; Harper, Jon A. ; Johnson, Dominic ; Allison, Rachal M

Meiotic recombination is initiated by DNA double-strand breaks (DSBs) created by Spo11, a type-II topoisomerase-like protein that becomes covalently linked to DSB ends. Whilst Spo11 oligos-the products of nucleolytic removal by Mre11-have been detected in several organisms, the lifetime of the covalent Spo11-DSB precursor has not been determined and may be subject to alternative processing. Here, we explore the activity of human Tyrosyl DNA Phosphodiesterase, TDP2-a protein known to repair DNA ends arising from abortive topoisomerase activity-on Spo11 DSBs isolated from S. cerevisiae cells. We demonstrate that TDP2 can remove Spo11 peptides from ssDNA oligos and dsDNA ends even in the presence of competitor genomic DNA. Interestingly, TDP2-processed DSB ends are refractory to resection by Exo1, suggesting that ssDNA generated by Mre11 may be essential in vivo to facilitate HR at Spo11 DSBs even if TDP2 were active. Moreover, although TDP2 can remove Spo11 peptides in vitro, TDP2 expression in meiotic cells was unable to remove Spo11 in vivo-contrasting its ability to aid repair of topoisomerase-induced DNA lesions. These results suggest that Spo11-DNA, but not topoisomerase-DNA cleavage complexes, are inaccessible to the TDP2 enzyme, perhaps due to occlusion by higher-order protein complexes at sites of meiotic recombination.

2024-10-01·European Journal of Medicinal Chemistry

Synthesis of furanotriterpenoids from betulin and evaluation of Tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitory properties of new semi-synthetic triterpenoids

Article

作者: Tolmacheva, Irina ; Eroshenko, Daria ; Lavrik, Olga ; Grishko, Victoria ; Chernyshova, Irina ; Nazarov, Mikhail

For the first time, a synthetic route for preparing lupane and oleanane derivatives with a hydrogenated furan ring as a cycle A of triterpene scaffold is described. Most of the synthesized compounds, furanoterpenoids and their synthetic intermediates, were non-toxic against the tested cancer and non-cancerous cell lines, and evinced significant inhibitory activity with IC₅₀ 1.0-9.0 μM in the tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition test. Lupane derivatives - 1-oxime 7, 1,10-seco-hydroxynitrile 11 and furanoterpenoid 14 - were selected as those expected to be the most promising compounds. The results of molecular modeling evinced the strongest binding of compound 11 to the active site of Tdp1 compared to the reference drug. Simultaneously, only compound 11 at subtoxic concentration (10 μM) produced a synergetic effect on the topotecan activity against HeLa-V cells.

项与 TDP1 相关的新闻（医药）

2024-10-13

·生物探索

Cell | TEX264驱动的选择性自噬促进DNA修复和细胞存活

引言 DNA 修复和自噬是维持细胞生存的两个关键生物学过程。DNA修复负责修复DNA损伤，确保基因组稳定；而自噬则负责清除细胞内多余的、受损的、错误折叠或聚集的蛋白质和细胞器，维持细胞稳态。拓扑异构酶 I (TOP1) 在DNA复制和转录中起着至关重要的作用，它通过切断DNA形成超螺旋结构，释放扭转应力。然而，TOP1与DNA形成的共价键——TOP1cc是一种有害的DNA损伤，会导致基因组不稳定和细胞死亡。TOP1cc修复主要依赖于酪氨酸DNA磷酸二酯酶 1 (TDP1) 介导的切除修复或MRE11核酶介导的DNA切割和切除修复【1】。然而，TOP1cc的修复过程与蛋白质降解途径的关系尚不清楚。自噬因子在DNA复制叉附近富集，表明自噬可能在DNA损伤修复中发挥作用。TEX264是一种保守的蛋白质，既是自噬受体，也与TOP1cc修复有关【2】。然而，TEX264是否通过自噬介导TOP1cc修复，目前尚不清楚。近日，来自英国牛津大学拉德克利夫医院的Kristijan Ramadan研究团队在Cell杂志上发表题为TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival的研究论文，该研究发现了TEX264介导的核吞噬作用在维持基因组稳定性和细胞存活中发挥关键作用。首先通过免疫共沉淀和蛋白质组学分析，研究人员发现自噬相关蛋白（如Beclin-1、TEX264、CHMP7、ATG7、SNAP29）在DNA复制叉处富集，并且这种富集在CPT（诱导DNA复制压力的化合物）处理后被显著增强，这表明自噬可能在响应 DNA 复制压力时发挥作用。接着，研究人员使用LysoIP技术分离溶酶体，并通过质谱分析其蛋白质组成。结果表明，CPT 处理后，许多DNA复制和核蛋白（如DNA聚合酶、MCM复合物蛋白、核孔复合物）被运送到溶酶体，表明溶酶体可能直接参与 DNA 损伤的清除。进一步，研究人员发现用CPT处理后，TOP1cc水平的恢复受到mTOR抑制剂Torin的促进，而自噬抑制剂ATG7的缺失则完全阻止了TOP1cc的修复，证明自噬是TOP1cc修复的关键途径。其他自噬相关蛋白，如syntaxin 17和RB1CC1，也参与了TOP1cc的降解和细胞对CPT的存活，说明自噬修复TOP1cc的过程是一个复杂的网络，涉及多个自噬相关蛋白。使用mCherry-TOP1-GFP报告系统证实了TOP1在低剂量CPT处理后进入溶酶体，表明 TOP1cc可以直接被溶酶体降解。通过分析γ-H2AX 和53BP1的定位，研究人员发现低剂量CPT诱导的DNA损伤主要表现为复制压力，而不是DNA 双链断裂。此外，研究人员发现ATR抑制剂VE-822强烈抑制了TOP1cc的运送，而ATM抑制剂KU-55933没有影响，这表明ATR在响应DNA复制压力和促进 TOP1cc 降解中起着关键作用。自噬抑制剂ATG7和syntaxin 17的缺失加剧了低剂量 CPT 处理后蛋白质聚集物的形成，说明自噬在防止蛋白质聚集物形成中发挥作用。最后，研究人员发现MRE11核酶的缺失强烈抑制了TOP1cc的运送，而MUS81和TDP1的缺失没有影响，表明MRE11核酶在将TOP1cc从核内运送到溶酶体中起着关键作用。使用 LysoIP-Seq技术分离溶酶体中的DNA片段，并通过测序分析其序列特征。结果表明，溶酶体中分离的DNA片段主要来自核内 DNA，且大部分来自内含子和着丝粒区域，表明溶酶体可以清除整个TOP1cc损伤，包括其蛋白质部分和相关的DNA片段。使用 TOP1cc 特异性抗体和LysoIP等技术证实了TOP1cc在低剂量CPT处理后在细胞质中的存在。这表明 TOP1cc可以从核内被运送到细胞质，并被溶酶体降解。图1 TEX264驱动的选择性自噬促进DNA修复和细胞存活（Credit: Cell）总之，这项研究证明了选择性自噬在DNA修复中的进化保守作用，并表明它对维持基因组稳定性和细胞存活至关重要。此外，该发现还表明，在治疗结直肠癌患者时， TEX264的表达水平与对伊立替康等TOP1抑制剂的化疗反应相关。参考文献 1. Pommier, Y. (2006). Topoisomerase I inhibitors: camptothecins and beyond. Nat. Rev. Cancer 6, 789–802. https://doi-org.libproxy1.nus.edu.sg/10.1038/nrc1977.7. Stingele, J., Bellelli, R., and Boulton, S.J. (2017). Mechanisms of DNA–protein crosslink repair. Nat. Rev. Mol. Cell Biol. 18, 563–573. 2. Fielden, J., Wiseman, K., Torrecilla, I., Li, S., Hume, S., Chiang, S.-C., Ruggiano, A., Narayan Singh, A., Freire, R., Hassanieh, S., et al. (2020). TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nat. Commun. 11, 1274. https://www-cell-com.libproxy1.nus.edu.sg/cell/fulltext/S0092-8674(24)00911-5 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2022-09-30

·生物谷

Nature：垃圾DNA的断裂和修复会影响身体对神经系统疾病的保护

在一项新的研究中，来自英国谢菲尔德大学等研究机构的研究人员发现垃圾DNA的断裂和修复会影响身体对神经系统疾病的保护，因此垃圾DNA可能会开启神经系统疾病的新疗法。相关研究结果发表在2022年9月29日的Nature期刊上，论文标题为“A mechanism for oxidative damage repair at gene regulatory elements”。在此之前，占基因组DNA 98%的垃圾DNA的修复在很大程度上被科学家们所忽视，但是这项新的研究发现，垃圾DNA比以前认为的更容易受到氧化基因组损伤的破坏。这对神经系统疾病的产生有着至关重要的影响。这些作者还确定了如何形成和修复氧化性断裂的途径。修复这些垃圾DNA的断裂对产生保护我们免受疾病的蛋白至关重要。具体而言，他们发现启动子通过一种由蛋白NuMA（也称为NUMA1）介导的过程免受氧化损伤。NuMA在转录起始点周围约100bp处表现出基因组占有率。它与RNA聚合酶II的起始形式、暂停释放因子（pause-release factor）和诸如TDP1之类的单链断裂修复（SSBR）组分结合。在氧化损伤后，这种结合在染色质上增加了，NuMA促进了TDP1在受损染色质上的富集。剔除NuMA会增加启动子的氧化损伤。NuMA通过限制RNA聚合酶II的聚ADP-核糖基化来促进转录，增加它的可用性并从启动子的暂停中释放。新生RNA的代谢标记确定了依赖NuMA进行转录的基因，包括即时早期反应基因。氧化应激是细胞代谢的一个不可避免的结果，可以受到饮食、生活方式和环境等因素的影响。从长远来看，氧化应激会对身体的细胞、蛋白和DNA造成损害，加快衰老过程，并促进诸如痴呆之类的神经系统疾病的产生。这些作者希望这项新的研究能够为开展进一步的研究铺平道路，从而可能有助于加快疾病生物标志物的检测，并允许进行早期干预，以帮助防止那些携带相关基因的人发生或发展神经系统疾病，如阿尔茨海默病和运动神经元疾病。论文通讯作者、谢菲尔德大学分子医学主任Sherif El-Khamisy教授说：“修复看不见的非编码基因组中的DNA断裂的意义将开辟一个全新的研究领域，包括治疗干预的新靶标和生物标志物。通过在治疗上靶向该途径的组分，它可能有助于我们推迟或治疗诸如痴呆之类的神经系统疾病。在此之前，对垃圾DNA的修复大体上被人们忽视了，但是我们的研究表明，它可能对神经系统疾病的发病和进展有重要影响。这项新的研究还表明，它可能对使癌症治疗更加有效有影响。”SSBR基因在不同大脑区域中的表达。图片来自Nature, 2022, doi:10.1038/s41586-022-05217-8。谢菲尔德大学健康寿命研究所联合主任Ilaria Bellantuono教授说：“这项新的研究很重要，因为它为能够确定新的药物以防止多种疾病同时产生并提高老年人的恢复能力铺平了道路。”这项新的研究也可能对新的癌症治疗产生重要影响，因为这些作者认为，抑制该途径的一个关键组分（NuMA）的活性可能有助于阻止不分裂的难以治疗的休眠癌细胞的生存。未来的研究预计将围绕与患者合作，探究与该途径相关的致病变体，并与行业合作开发治疗性干预措施以帮助那些患有常见神经疾病的人，比如痴呆、阿尔茨海默病、运动神经元疾病和亨廷顿舞蹈病。参考资料：1. Swagat Ray et al. A mechanism for oxidative damage repair at gene regulatory elements. Nature, 2022, doi:10.1038/s41586-022-05217-8.2. Breaks in 'junk' DNA give scientists new insight into neurological disordershttps://medicalxpress.com/news/2022-09-junk-dna-scientists-insight-neurological.html

基因疗法