更新于：2024-11-01

RUVBL2 x RUVBL1

更新于：2024-11-01

基本信息

关联

项与 RUVBL2 x RUVBL1 相关的药物

DS-4950

靶点

RUVBL1 x RUVBL2

作用机制

RUVBL1 抑制剂 [+1]

在研机构

Daiichi Sankyo Co., Ltd. [+1]

原研机构

Daiichi Sankyo Co., Ltd. [+1]

在研适应症

急性髓性白血病

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

CB-6644

靶点

RUVBL1 x RUVBL2

作用机制

RUVBL1 抑制剂 [+1]

在研机构

Cleave Therapeutics, Inc.

原研机构

Cleave Therapeutics, Inc.

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 RUVBL2 x RUVBL1 相关的临床结果

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100 项与 RUVBL2 x RUVBL1 相关的转化医学

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0 项与 RUVBL2 x RUVBL1 相关的专利（医药）

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150

项与 RUVBL2 x RUVBL1 相关的文献（医药）

2024-09-04·Cancer Research

RUVBL1/2 Blockade Targets YTHDF1 Activity to Suppress m6A-Dependent Oncogenic Translation and Colorectal Tumorigenesis

Article

作者: Zhou, Qiming ; Kang, Wei ; Pan, Yasi ; Wong, Chi Chun ; Chen, Danyu ; Liang, Cong ; Cheung, Alvin H.-K. ; Wei, Qinyao ; Ji, Fenfen ; Yu, Jun ; Cheung, Henley ; Lau, Harry C.-H. ; Yang, Zhenjie ; Chen, Huarong ; Huang, Pingmei

AbstractThe N6-methyladenosine (m6A) RNA-binding protein YTHDF1 is frequently overexpressed in colorectal cancer and drives chemotherapeutic resistance. To systematically identify druggable targets in colorectal cancer with high expression of YTHDF1, this study used a CRISPR/Cas9 screening strategy that revealed RUVBL1 and RUVBL2 as putative targets. RUVBL1/2 were overexpressed in primary colorectal cancer samples and represented independent predictors of poor patient prognosis. Functionally, loss of RUVBL1/2 preferentially impaired the growth of YTHDF1-high colorectal cancer cells, patient-derived primary colorectal cancer organoids, and subcutaneous xenografts. Mechanistically, YTHFD1 and RUVBL1/2 formed a positive feedforward circuit to accelerate oncogenic translation. YTHDF1 bound to m6A-modified RUVBL1/2 mRNA to promote translation initiation and protein expression. Coimmunoprecipitation and mass spectrometry identified that RUVBL1/2 reciprocally interacted with YTHDF1 at 40S translation initiation complexes. Consequently, RUVBL1/2 depletion stalled YTHDF1-driven oncogenic translation and nascent protein biosynthesis, leading to proliferative arrest and apoptosis. Ribosome sequencing revealed that RUVBL1/2 loss impaired the activation of MAPK, RAS, and PI3K-AKT signaling induced by YTHDF1. Finally, the blockade of RUVBL1/2 by the pharmacological inhibitor CB6644 or vesicle-like nanoparticle-encapsulated siRNAs preferentially arrested the growth of YTHDF1-expressing colorectal cancer in vitro and in vivo. Our findings show that RUVBL1/2 are potential prognostic markers and druggable targets that regulate protein translation in YTHDF1-high colorectal cancer.Significance: RUVBL1/2 inhibition is a therapeutic strategy to abrogate YTHDF1-driven oncogenic translation and overcome m6A dysregulation in colorectal cancer.

2024-09-01·Gut

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2

Article

作者: Vogt, Markus ; Cruz Garcia, Yiliam ; Rosenfeldt, Mathias ; Hofstetter, Julia ; Kuybu, Filiz ; Martin, Benedikt ; Adhikari, Bikash ; Rocca, Yamila ; Eilers, Martin ; Hamann, Anton ; Hauck, Theresa ; Wolf, Elmar ; Gasteiger, Georg ; Diefenbacher, Markus ; Schneider, Katharina ; Erhard, Florian ; Knapp, Stefan ; Grysczyk, Lara ; Vos, Seychelle M ; Saur, Dieter ; Dudvarski Stankovic, Nevenka ; Wiegering, Armin ; Gebhardt-Wolf, Anneli

ObjectiveThe hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC).DesignTo identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumours in mice.ResultsUnexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immunoevasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer.ConclusionOne implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.

2024-08-14·mBio

Molecular insights into type I interferon suppression and enhanced pathogenicity by species B human adenoviruses B7 and B14

Article

作者: Pelka, Peter ; Akkerman, Nikolas ; Helwer, Rafe ; Graves, Drayson ; Fulham, Lauren

ABSTRACTHuman adenoviruses (HAdVs) are small DNA viruses that generally cause mild disease. Certain strains, particularly those belonging to species B HAdVs, can cause severe pneumonia and have a relatively high mortality rate. Little is known about the molecular aspects of how these highly pathogenic species affect the infected cell and how they suppress innate immunity. The present study provides molecular insights into how species B adenoviruses suppress the interferon signaling pathway. Our study shows that these viruses, unlike HAdV-C2, are resistant to type I interferon. This resistance likely arises due to the highly efficient suppression of interferon-stimulated gene expression. Unlike in HAdV-C2, HAdV-B7 and B14 sequester STAT2 and RNA polymerase II from interferon-stimulated gene promoters in infected cells. This results in suppressed interferon- stimulated gene activation. In addition, we show that RuvBL1 and RuvBL2, cofactors important for RNA polymerase II recruitment to promoters and interferon-stimulated gene activation, are redirected to the cytoplasm forming high molecular weight complexes that, likely, are unable to associate with chromatin. Proteomic analysis also identified key differences in the way these viruses affect the host cell, providing insights into species B-associated high pathogenicity. Curiously, we observed that at the level of protein expression changes to the infected cell, HAdV-C2 and B7 were more similar than those of the same species, B7 and B14. Collectively, our study represents the first such study of innate immune suppression by the highly pathogenic HAdV-B7 and B14, laying an important foundation for future investigations.IMPORTANCEHuman adenoviruses form a large family of double-stranded DNA viruses known for a variety of usually mild diseases. Certain strains of human adenovirus cause severe pneumonia leading to much higher mortality and morbidity than most other strains. The reasons for this enhanced pathogenicity are unknown. Our study provides a molecular investigation of how these highly pathogenic strains might inactivate the interferon signaling pathway, highlighting the lack of sensitivity of these viruses to type I interferon in general while providing a global picture of how viral changes in cellular proteins drive worse disease outcomes.

项与 RUVBL2 x RUVBL1 相关的新闻（医药）

2024-02-13

·生物探索

Cell Discov | 冷冻电镜揭示的SRCAP复合体与核小体结合的高分辨率结构

引言组蛋白变体H2A.Z在启动子上发现并调节转录。ATP依赖性染色质重塑器SRCAP复合体(SRCAP-C)促进标准组蛋白H2A.Z-H2B二聚体被H2A–H2B取代。2024年2月8日，复旦大学徐彦辉及Wang Li共同通讯在Cell Discovery（IF 33.5）在线发表题为“Structural insights into histone exchange by human SRCAP complex”的研究论文，该研究确定了人类SRCAP-C与含H2A的核小体结合的结构。在真核细胞中，基因组DNA包裹在组蛋白八聚体周围，在基因组上产生排列的核小体。典型核小体包含四个组蛋白H2A、H2B、H3和H4的两个拷贝。为了实现功能调节，ATP依赖性染色质重塑复合体(重塑复合体)改变核小体的组成和沿DNA的位置。染色质重塑复合物根据其催化ATP酶的异同可分为4个家族：模仿开关(ISWI)、染色质结构域解旋酶DNA结合(CHD)、开关/sucrose不可发酵(SWI/ SNF)和肌醇营养不良80 (INO80)。其中两种重塑蛋白由单个亚基(CHD家族)或几个亚基(ISWI家族)组成。相比之下，SWI/SNF和INO80家族是多亚基复合物，除了超家族II解旋酶样运动亚基外，还含有肌动蛋白和肌动蛋白相关蛋白(ARPs)以及其他具有不同功能的重塑蛋白特异性亚基。人类染色质重塑子SNF2相关CPB激活蛋白(SRCAP)复合物(SRCAP-C)及其酵母对应物SWR1复合物(SWR-C)属于INO80染色质重塑子家族。SRCAP-C和SWR-C可以用H2A.Z-H2B二聚体以ATP依赖的方式取代H2A-H2B二聚体，这一过程可能需要组蛋白伴侣。生成的H2A.Z含核小体富集于几乎所有常染色质基因的启动子区域，并参与转录和其他过程的调控，如DNA复制、DNA修复和染色体分离。在真核细胞中，H2A.Z主要存在于它位于启动子的远端，在RNAPII的起始和延伸中起关键作用。H2A.Z在复制起点也广泛富集，并通过调节早期复制起点的起始和复制时间与DNA复制直接相关。此外，研究表明，协调H2A.Z双链断裂(DSBs)中的动力学对DNA修复至关重要。H2A.Z在染色体分离过程中也起着至关重要的作用，以维持基因组处于稳定状态。与其他染色质重塑子不同，SWR-C与核小体结合并诱导DNA展开和重新包裹，但不产生净DNA易位，表现出一种典型特征。核小体结合的SRCAP-C的整体结构（Credit: Cell Discovery）人SRCAP-C是一种~1-MDa复合物，由SRCAP、YL1、RUVBL1、RUVBL2、ARP6、ZNHIT1、DMAP1、ACTL6A、ACTB和YEATS4等10个亚基组成，酵母SRCAP-C由10个相同的亚基组成，分别为Swr1、Swc2、RvB1、RvB2、ARP6、Swc6、Swc4、Arp4、Actin、Yaf9和另外4个酵母特异性亚基Swc3、Swc5、Swc7和Bdf1。先前的研究已经揭示了酵母SWR-C、人SRCAP-C和核小体结合酵母SWR-C在ATP类似物ADP-BeFx存在下的结构。SWR-C含有RuvBL蛋白的异六聚体，Swr1中的插入物通过RuvBL六聚体延伸。Swr1的ATP酶结构域在超螺旋位置(SHL) 2上抓住DNA，导致DNA在ADP-BeFx结合状态下移位1bp。此外，进入DNA部分被解开，组蛋白核心“弯曲”。与酵母SWR-C相比，SRCAP-C采用了大致相似的结构，包含一个带有两个独立臂的环状“头”。该研究测定了核小体结合的SRCAP-C在不同核苷酸结合状态下的结构，并进行了结构引导染色质免疫沉淀测序(ChIP-seq)分析，以测试ZNHIT1对H2A.Z在体内掺入的影响。SRCAP-C介导的Z交换。SRCAP亚基集成了一个6亚基肌动蛋白相关蛋白(ARP)模块和一个含ATP酶的马达模块。ATP酶相关的ARP模块沿DNA包围核小体的一半，并可能抑制净DNA易位，这是SRCAP-C的独特特征。motor模块在载脂蛋白(无核苷酸)、ADP结合和ADP-BeFx结合状态下采用不同的核小体结合模式，表明ATP酶驱动的运动通过解开进入DNA的包裹使H2A-H2B不稳定，并通过ZNHIT1亚基将H2A-H2B拉出核小体。结构导向的染色质免疫沉淀测序分析证实了H2A接触ZNHIT1维持H2A.Z基因组上占用率的必要性。该研究为SRCAP-C介导的H2A-H2A.Z交换机制提供了结构性的见解。原文链接https://www.nature.com/articles/s41421-023-00640-1责编|探索君排版|探索君文章来源|“iNature”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Science最新发布：全世界最前沿的125个科学问题热文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Nature | 癌症与神经系统的致命舞蹈

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