更新于：2024-11-01

MCM7

更新于：2024-11-01

基本信息

别名

CDC47、CDC47 homolog、DNA replication licensing factor MCM7

+ [5]

简介

Acts as component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built (PubMed:32453425, PubMed:34694004, PubMed:34700328, PubMed:35585232, PubMed:25661590, PubMed:9305914). The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity (PubMed:32453425). Required for S-phase checkpoint activation upon UV-induced damage.

关联

项与 MCM7 相关的药物

MCM7 inhibitors(Enkang Pharmaceutical)

MCM7 抑制剂(恩康药业)

靶点

MCM7

作用机制

MCM7抑制剂

在研机构-

原研机构

恩康药业科技(广州)有限公司

在研适应症-

非在研适应症

肿瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MCM7 相关的临床结果

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100 项与 MCM7 相关的转化医学

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0 项与 MCM7 相关的专利（医药）

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667

项与 MCM7 相关的文献（医药）

2024-09-01·Acta Pharmaceutica Sinica B

Beyond ribosomal function: RPS6 deficiency suppresses cholangiocarcinoma cell growth by disrupting alternative splicing

Article

作者: Dai, Lunzhi ; Zhang, Yong ; Lin, Yanyan ; Yuan, Jinqiu ; Zhang, Wenhua ; Zhang, Jinduo ; Bai, Mingzhen ; Mi, Ningning ; Leung, Joseph W ; zhang, Jinduo ; Ma, Haidong ; Ding, Liyun ; Yao, Jia ; Fu, Wenkang ; Meng, Wenbo ; Yue, Ping ; Tian, Liang ; Leung, Joseph W. ; Huang, Chongfei ; Gao, Long ; Ren, Yanxian

Cholangiocarcinoma (CCA) is a bile duct malignancy with a dismal prognosis. This study systematically investigated the role of the ribosomal protein S6 (RPS6) gene, which is dependent in CCA. We found that RPS6 upregulation in CCA tissues was correlated with a poor prognosis. Functional investigations have shown that alterations in RPS6 expression, both gain- and loss-of function could affect the proliferation of CCA cells. In xenograft tumor models, RPS6 overexpression enhances tumorigenicity, whereas RPS6 silencing reduces it. Integration analysis using RNA-seq and proteomics elucidated downstream signaling pathways of RPS6 depletion by affecting the cell cycle, especially DNA replication. Immunoprecipitation followed by mass spectrometry has identified numerous spliceosome complex proteins associated with RPS6. Transcriptomic profiling revealed that RPS6 affects numerous alternative splicing (AS) events, and combined with RNA immunoprecipitation sequencing, revealed that minichromosome maintenance complex component 7 (MCM7) binds to RPS6, which regulates its AS and increases oncogenic activity in CCA. Targeting RPS6 with vivo phosphorodiamidate morpholino oligomer (V-PMO) significantly inhibited the growth of CCA cells, patient-derived organoids, and subcutaneous xenograft tumor. Taken together, the data demonstrate that RPS6 is an oncogenic regulator in CCA and that RPS6-V-PMO could be repositioned as a promising strategy for treating CCA.

2024-09-01·Life Sciences

RNF8-mediated multi-ubiquitination of MCM7: Linking disassembly of the CMG helicase with DNA damage response in human cells

Article

作者: Luo, Jing ; Fu, Zhisong ; Sun, Qianqian ; Zhao, Wenhui ; Li, Shirui ; Sui, Yaqi ; Zhou, Rui

DNA damage causes genomic instability. To maintain genome integrity, cells have evolved DNA damage response, which is involved in replication fork disassembly and DNA replication termination. However, the mechanism underlying the regulation of replication fork disassembly and its connection with DNA damage repair remain elusive. The CMG-MCM7 subunit ubiquitination functions on the eukaryotic replication fork disassembly at replication termination. Until now, only ubiquitin ligases CUL2^LRR1 have been reported catalyzing MCM7 ubiquitination in human cells. This study discovered that in human cells, the ubiquitin ligase RNF8 catalyzes K63-linked multi-ubiquitination of MCM7 at K145 both in vivo and in vitro. The multi-ubiquitination of MCM7 is dynamically regulated during the cell cycle, primarily presenting on chromatin during the late S phase. Additionally, MCM7 polyubiquitylation is promoted by RNF168 and BRCA1 during DNA replication termination. Upon DNA damage, the RNF8-mediated polyubiquitination of MCM7 decreased significantly during the late S phase. This study highlights the novel role of RNF8-catalyzed polyubiquitination of MCM7 in the regulation of replication fork disassembly in human cells and linking it to DNA damage response.

2024-08-01·Theriogenology

Melatonin reduces oxidative stress and improves follicular morphology in feline (Felis catus) vitrified ovarian tissue

Article

作者: Colombo, Martina ; Alkali, Isa Mohammed ; Luvoni, Gaia Cecilia

Ovarian tissue vitrification is associated with multiple events that promote accumulation of ROS (reactive oxygen species) which culminate in follicular apoptosis. Thus, this study was aimed at evaluating the role of melatonin in vitrification and culture of feline (Felis catus) ovarian tissue. In phase 1, domestic cat ovaries were fragmented into equal circular pieces of 1.5 mm diameter by 1 mm thickness and divided into four groups (fresh control and 3 treatments). The treatments were exposed to vitrification solutions supplemented with melatonin at 0 M, 10^-9 M, and 10^-7 M, then vitrified-warmed, histologically evaluated and assayed for ROS. Consequently, phase 2 experiment was designed wherein ovarian fragments were divided into two groups. One group was exposed to vitrification solution without melatonin and the other with 10^-7 M melatonin supplementation, then vitrified-warmed and cultured for ten days with fresh ovarian fragments as control prior to assessment for histology, immunohistochemistry (Ki-67, MCM-7 and caspase-3) and ROS. Concentration of ROS was lower (p = 0.0009) in 10^-7 M supplemented group in addition to higher proportion of grade 1 follicles. After culture, proportions of intact and activated follicles were higher (p < 0.05) in melatonin supplemented group evidenced by higher expression of Ki-67 and MCM-7. Follicular apoptosis was lower in melatonin supplemented group. In conclusion, melatonin at 10^-7 M concentration preserved follicular morphological integrity while reducing ROS concentration in vitrified-warmed feline ovarian tissue. It has also promoted the follicular viability and activation with reduced apoptosis during in vitro culture of vitrified-warmed feline ovarian tissue.

项与 MCM7 相关的新闻（医药）

2023-02-08

·生物谷

Science子刊：郑萍团队阐明新型LncRNA维持多能干细胞基因组稳态新机制

该研究鉴定了在小鼠胚胎干细胞（mESCs）中特异表达的全新长非编码RNA-LncRNA NONMMUT028956（简写为Lnc956）。对该LncRNA的系统研究发现，它不仅参与复制压力下mESCs 多能干细胞（Pluripotent stem cells，PSCs）因在体外具无限增殖和分化为不同类型细胞的潜能，在再生医学领域中颇具应用前景，也成为目前临床上最具潜能的成药细胞。PSCs制备过程中的标准化、规模化及细胞质量稳定性是走向临床应用的先决条件，但人PSCs在体外扩增培养过程中，易出现遗传和表观遗传的变异，严重阻碍了PSCs的临床应用。因此，研究PSCs遗传物质稳定性维持机理，是寻找改善策略、突破应用瓶颈的关键。 PSCs基因组的突变率远低于分化细胞。中国科学院昆明动物研究所郑萍团队与合作者的前期研究表明，PSCs利用不同于体细胞的特殊机制，有效调控基因组稳定。郑萍团队前期已鉴定了PSCs在DNA复制、DNA损伤修复中的一些特殊分子及作用机制。近日，中国科学院昆明动物研究所郑萍团队在 Science 子刊 Science Avances 上发表了两篇研究论文，论文分别以：Lnc956-TRIM28-HSP90B1 complex on replication forks promotes CMG helicase retention to ensure stem cell genomic stability and embryogenesis 和 Lnc956 regulates mouse embryonic stem cell differentiation in response to DNA damage in a p53-independent pathway 为题。该研究鉴定了在小鼠胚胎干细胞（mESCs）中特异表达的全新长非编码RNA-LncRNA NONMMUT028956（简写为Lnc956）。对该LncRNA的系统研究发现，它不仅参与复制压力下mESCs复制小体稳定的维持，而且还监控mESCs基因组的质量，从而确保mESCs基因组稳态。长非编码RNA（lncRNA）在多种生物学功能中起重要作用。由于技术手段的限制，目前尚未有发现复制叉上具功能性长非编码RNA的报道。研究团队利用前期研发的分离新生DNA链上（即复制叉）RNA技术（isolate RNAs on nascent DNA，iROND），首次鉴定了ESCs复制叉上特异的新的功能性LncRNA-Lnc956。对该LncRNA的研究发现，当复制压力发生时，Lnc956能有效聚集到复制叉上，并大量招募Trim28和Hsp90b1聚集于复制叉形成复合体。Trim28直接与DNA复制解旋酶复合体MCM2-7相互作用，拉近了Lnc956-Trim28-Hsp90b1复合体与MCM2-7复合体之间的物理距离，使分子伴侣Hsp90b1通过GTP水解活性作用于MCM7，阻碍MCM7进行K48和K63泛素化（MCM7泛素化会导致复制小体解离），从而使复制小体能在一定程度复制压力情况下得以稳定，保持了基因组的完整性。研究团队还发现Lnc956缺失会导致小鼠胚胎部分致死。致死原因主要是胚胎细胞大量扩增过程中，细胞出现明显基因组不稳定现象，并导致胞质DNA水平显著增加，引起较严重的炎症反应。总之，该研究成果迄今首次发现了小鼠多能干细胞复制叉上特异性功能性长非编码RNA-Lnc956，并揭示了Lnc956维持多能干细胞基因组稳定和促进胚胎发育的分子机制。 Lnc956维持复制叉稳定促进多能干细胞基因组稳定的分子机制有效清除基因组损伤的细胞个体，是干细胞维持群体基因组稳定的重要方式。p53是目前已知唯一的干细胞基因组质量监控分子。p53通过在转录水平上抑制多能性调控网络关键基因的表达，激活分化调控网络基因的转录，使PSCs快速启动分化和凋亡，确保PSCs的基因组质量。除了p53通路，是否还存在其他独立的机制调控损伤干细胞的清除，值得进一步研究。研究团队针对新鉴定的LncRNA-Lnc956在干细胞质量控制中发挥的作用做了深入探索。利用多种DNA损伤药物处理、分化、凋亡、单克隆形成、克隆竞争性和转录组学等方法对该LncRNA功能研究后，研究团队发现缺失Lnc956的ESCs在受到DNA损伤后不易启动分化和凋亡，提示Lnc956参与DNA损伤后ESCs的分化和凋亡。但是，Lnc956缺失的ESC中，p53通路的激活和功能未受影响，提示p53没有介导Lnc956的调控作用。为探究Lnc956分子水平上具体作用机理，研究团队利用In vitro/in vivo RNA pull down、蛋白质质谱及RNA免疫共沉淀等技术鉴定出与Lnc956相互作用的靶蛋白-KLF4。通过机制分析发现，在未受DNA损伤时，Lnc956与KLF4无相互作用。而在基因组受损后，DNA损伤反应通路的核心激酶ATM激活，ATM活化Mettl3（调控RNA m6A修饰），使Lnc956发生m6A修饰。发生m6A修饰的Lnc956大量结合干性维持关键蛋白KLF4。Lnc956-KLF4结合体滞留KLF4蛋白，阻止KLF4蛋白对ESCs多能性的调控，阻止KLF4蛋白结合到DNA上行使干性调控功能，使基因组损伤的干细胞快速发生分化，得以清除。 Lnc956-KLF4通路不依赖p53，和p53通路平行，共同对干细胞基因组质量进行监控。因此，当ESCs受到DNA损伤应激时，磷酸化的ATM信号通路可分别激活p53和Lnc956-KLF4两条通路，使未受DNA损伤修复的ESCs快速发生分化和凋亡，高效清除受损ESCs，防止受损ESCs传递到子代，确保了ESCs遗传物质的稳定性和安全性。 p53和Lnc956协调调控ESCs质量控制的工作模型

2023-01-15

·生物谷

Cell：我国科学家领衔解析出人类MCM2-7复合物的三维结构，有望开发出更安全的抗癌药物

在一项新的研究中，来自中国香港大学、香港科技大学、香港理工大学和法国居里研究所的研究人员发现了人类MCM2-7复合物调节复制起始的新机制。这一发现有助于开发一种新的有效抗癌策略，有可能选择性地杀死癌细胞。相关研究结果发表在2023年1月5日的Cell期刊上，论文标题为“The human pre-replication complex is an open complex”。人类的生命始于母体子宫中的一个受精卵。这个受精卵通过细胞分裂进行增殖，发育成我们的多细胞身体。在每次细胞分裂过程中，我们的基因组DNA，即遗传信息的蓝图，被准确地复制。每个细胞携带大约2米长的DNA，组装成23对染色体。在我们的一生中（约70年），我们的身体将合成超过一光年---光在一年里传播的距离---长的DNA，约1016米。这种复制过程要求DNA双链首先解链，然后分离成两个单链模板，供DNA聚合酶合成为互补链。这种过程的任何错误调节都会导致可怕的后果，如肿瘤发生和遗传性的基因疾病。论文共同通讯作者、香港大学生物科学学院助理教授Yuanliang Zhai博士说，“揭开DNA复制的秘密是理解生命之谜的关键。解析DNA复制机器的结构是告知其分子功能的关键，毕竟眼见为实。”自1953年James Watson和Francis Crick确定了DNA的结构以来，DNA双链最初是如何解链的，一直是生物学家的一个长期问题。在真核生物中，负责在复制过程中解开DNA双链的酶最初被康奈尔大学的Bik-Kwoon Tye教授在1983年确定为来自酿酒酵母的小染色体维持蛋白复合物（minichromosome maintenance protein complex, MCM）基因。六个MCM基因--- MCM2至MCM7（MCM2-7）---的产物形成一种六亚基的环状复合物，作为DNA解链机器---DNA复制螺旋酶---的催化核心。在细胞中，为了启动DNA复制，MCM2-7复合物必须首先在每条染色体的数千个位点上组装成环绕双链DNA的头对头双六聚体（double hexamer, DH）。在大量组装好的MCM2-7 DH中，只有其中的一个亚群会被最终选中并转化为强大的复制性螺旋酶，用于DNA解旋。人们认为，MCM2-7 DH可以直接破坏DNA的稳定性，以触发双链DNA的初始打开。然而，它的基本机制在很大程度上仍然是未知的。为了解决这个问题，这些作者试图使用一种前沿技术---低温电镜（cryo-EM）来观察MCM2-7 DH的原子细节。2015年，他们首次解析出从酵母中分离出来的MCM2-7 DH的3.8埃的低温电镜结构（Nature, 2015, doi:10.1038/nature14685）。不幸的是，捕获的DNA是不稳定的，未能告知MCM2-7 DH结合的DNA双链的状态。在这项新的研究中，他们成功地从体外培养的人类细胞中纯化出MCM2-7 DH，并确定了它在分辨率为2.59埃时的结构。这种高分辨率的结构清楚地展示了MCM2-7复合物如何破坏DNA的稳定性，从而在两个偶联的MCM2-7六聚体的连接处导致DNA双链的初始打开。他们还发现，MCM2-7 DH在整个人类基因组的数万个位点处结合到DNA上，这些位点与活跃的转录位点相互排斥。此外，当这种最初的开放结构受到干扰时，MCM2-7 DH不能再组装到DNA上，导致DNA复制的启动受到完全抑制。图片来自Cell, 2023, doi:10.1016/j.cell.2022.12.008。论文共同通讯作者、香港大学生物科学学院助理教授Shangyu Dang博士说，“这种原子分辨率的低温电镜结构使我们能够直接观察到最初的DNA解链，这对我们了解DNA复制的分子机制至关重要。这项新的研究也显示了合作的重要性。需要具有互补专长的研究团队的努力来回答基本的生物学问题。”DNA复制已经成为几种治疗癌症药物的靶标。然而，现有的药物不分青红皂白地杀死所有分裂的细胞，因为正常细胞和癌细胞都必须复制它们的DNA来实现细胞增殖。因此，这些药物的特异性引起了人们对这些抗癌化疗药物的严重关切。一种更理想的替代选择是抑制DNA复制的启动，使正常细胞停滞在G1期（第一生长期）或退出细胞周期进入G0状态（静止期）；但癌细胞将经历凋亡。因此，抑制复制启动可以作为一种新的、有效的抗癌策略，具有选择性杀死癌细胞的潜力。这项新研究的结果提供了人类起始前复合物---MCM2-7复合物---的高分辨率结构和机理信息，将来可用于开发靶向MCM2-7复合物的无毒抗癌药物。参考资料：Jian Li et al. The human pre-replication complex is an open complex. Cell, 2023, doi:10.1016/j.cell.2022.12.008.

临床结果临床1期