TEX264

更新于：2025-05-07

基本信息

别名

FLJ13935、Putative secreted protein Zsig11、testis expressed 264, ER-phagy receptor

+ [3]

简介

Major reticulophagy (also called ER-phagy) receptor that acts independently of other candidate reticulophagy receptors to remodel subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover (PubMed:31006537, PubMed:31006538). The ATG8-containing isolation membrane (IM) cradles a tubular segment of TEX264-positive ER near a three-way junction, allowing the formation of a synapse of 2 juxtaposed membranes with trans interaction between the TEX264 and ATG8 proteins (PubMed:31006537). Expansion of the IM would extend the capture of ER, possibly through a 'zipper-like' process involving continued trans TEX264-ATG8 interactions, until poorly understood mechanisms lead to the fission of relevant membranes and, ultimately, autophagosomal membrane closure (PubMed:31006537). Also involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis: acts by bridging VCP/p97 to covalent DNA-protein cross-links (DPCs) and initiating resolution of DPCs by SPRTN (PubMed:32152270).

关联

100 项与 TEX264 相关的临床结果

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100 项与 TEX264 相关的转化医学

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0 项与 TEX264 相关的专利（医药）

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项与 TEX264 相关的文献（医药）

2025-03-04·Autophagy

Autophagy as a way to remove DNA lesions

Article

作者: Lei, Yuchen ; Klionsky, Daniel J.

Type I topoisomerases (TOP1) are critical to remove the topological stress when DNA double strands are unwound. The TOP1 cleavage complexes (TOP1cc) are normally transient, and the stabilization of TOP1cc by its inhibitors, such as camptothecin (CPT), may lead to DNA damage and become cytotoxic. The proteasome pathway degrades trapped TOP1, which is necessary for the repair machinery to gain access to the DNA; however, this process is mainly described when the CPT concentration is high, at levels which are clinically unachievable. In a recently published study, Lascaux et al. identify macroautophagy/autophagy as a new pathway to remove DNA lesions upon clinically relevant low-dose CPT treatment. The autophagy receptor TEX264 binds to TOP1 and brings this protein and its bound DNA fragments to the phagophore; subsequently, they are ultimately delivered to the lysosome for degradation. This study demonstrates the role of autophagy in maintaining genome stability from a new perspective and reveals potential targets to deal with the resistance to TOP1cc inhibitors during cancer treatment.

2025-01-01·Trends in Biochemical Sciences

TEX264-mediated selective autophagy directs DNA damage repair

Article

作者: Suzuki, Sho W ; Qi, Yuxia

DNA is constantly subject to damage from endogenous and exogenous factors, leading to mutations and disease. While DNA is traditionally repaired in the nucleus, Lascaux et al. reveal a novel role for the lysosome in DNA repair, demonstrating that topoisomerase 1 (TOP1) cleavage complex (TOP1cc) DNA lesions are degraded via TEX264-mediated selective autophagy.

2024-10-01·Cell

TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival

Article

作者: Torrecilla, Ignacio ; Koukouravas, Stelios ; Trugenberger, Camilla ; Maughan, Tim ; Otten, Cecile ; Vendrell, Iolanda ; Popović, Marta ; Yang, Hongbin ; Song, Wei ; Ruggiano, Annamaria ; Carrique, Loïc ; Domingo, Enric ; Tribble, Sara ; Fischer, Roman ; Ngeow, Joanne ; Milošević, Ira ; Ng, Alvin Wei Tian ; Bancroft, James ; Lascaux, Pauline ; Antičević, Ivan ; D’Angiolella, Vincenzo ; Peron, Cristiano ; Aljarbou, Ftoon ; Johnson, Errin ; Raimundo, Nuno ; Hoslett, Gwendoline ; Deangeli, Giulio ; Ramadan, Kristijan ; Zhao, Yichen ; D'Angiolella, Vincenzo

DNA repair and autophagy are distinct biological processes vital for cell survival. Although autophagy helps maintain genome stability, there is no evidence of its direct role in the repair of DNA lesions. We discovered that lysosomes process topoisomerase 1 cleavage complexes (TOP1cc) DNA lesions in vertebrates. Selective degradation of TOP1cc by autophagy directs DNA damage repair and cell survival at clinically relevant doses of topoisomerase 1 inhibitors. TOP1cc are exported from the nucleus to lysosomes through a transient alteration of the nuclear envelope and independent of the proteasome. Mechanistically, the autophagy receptor TEX264 acts as a TOP1cc sensor at DNA replication forks, triggering TOP1cc processing by the p97 ATPase and mediating the delivery of TOP1cc to lysosomes in an MRE11-nuclease- and ATR-kinase-dependent manner. We found an evolutionarily conserved role for selective autophagy in DNA repair that enables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients.

项与 TEX264 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/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/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

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