更新于：2024-09-19

MORC2

更新于：2024-09-19

基本信息

别名

AC004542.C22.1、ATPase MORC2、KIAA0852

+ [6]

简介

Essential for epigenetic silencing by the HUSH (human silencing hub) complex. Recruited by HUSH to target site in heterochromatin, the ATPase activity and homodimerization are critical for HUSH-mediated silencing (PubMed:28581500, PubMed:29440755, PubMed:32693025). Represses germ cell-related genes and L1 retrotransposons in collaboration with SETDB1 and the HUSH complex, the silencing is dependent of repressive epigenetic modifications, such as H3K9me3 mark. Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression (PubMed:29211708). During DNA damage response, regulates chromatin remodeling through ATP hydrolysis. Upon DNA damage, is phosphorylated by PAK1, both colocalize to chromatin and induce H2AX expression. ATPase activity is required and dependent of phosphorylation by PAK1 and presence of DNA (PubMed:23260667). Recruits histone deacetylases, such as HDAC4, to promoter regions, causing local histone H3 deacetylation and transcriptional repression of genes such as CA9 (PubMed:20225202, PubMed:20110259). Exhibits a cytosolic function in lipogenesis, adipogenic differentiation, and lipid homeostasis by increasing the activity of ACLY, possibly preventing its dephosphorylation (PubMed:24286864).

关联

100 项与 MORC2 相关的临床结果

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100 项与 MORC2 相关的转化医学

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0 项与 MORC2 相关的专利（医药）

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项与 MORC2 相关的文献（医药）

2024-06-03·Brain

Morc2a variants cause hydroxyl radical-mediated neuropathy and are rescued by restoring GHKL ATPase

Article

作者: Hwang, Daehee ; Jung, Choonkyun ; Song, Sumin ; Choi, Byung-Ok ; Kim, Gap-Don ; Hyeon, Do Young ; Chung, Hye Yoon ; Han, Jeong Pil ; Lee, Jeong Hyeon ; Yeom, Su Cheong ; Nam, Soo Hyun ; Lee, Geon Seong

AbstractMutations in the Microrchidia CW-type zinc finger 2 (MORC2) GHKL ATPase module cause a broad range of neuropathies, such as Charcot-Marie-Tooth disease type 2Z; however, the aetiology and therapeutic strategy are not fully understood. Previously, we reported that the Morc2a p.S87L mouse model exhibited neuropathy and muscular dysfunction through DNA damage accumulation.In the present study, we analysed the gene expression of Morc2a p.S87L mice and designated the primary causing factor. We investigated the pathological pathway using Morc2a p.S87L mouse embryonic fibroblasts and human fibroblasts harbouring MORC2 p.R252W. We subsequently assessed the therapeutic effect of gene therapy administered to Morc2a p.S87L mice.This study revealed that Morc2a p.S87L causes a protein synthesis defect, resulting in the loss of function of Morc2a and high cellular apoptosis induced by high hydroxyl radical levels. We considered the Morc2a GHKL ATPase domain as a therapeutic target because it simultaneously complements hydroxyl radical scavenging and ATPase activity. We used the adeno-associated virus (AAV)-PHP.eB serotype, which has a high CNS transduction efficiency, to express Morc2a or Morc2a GHKL ATPase domain protein in vivo. Notably, AAV gene therapy ameliorated neuropathy and muscular dysfunction with a single treatment. Loss-of-function characteristics due to protein synthesis defects in Morc2a p.S87L were also noted in human MORC2 p.S87L or p.R252W variants, indicating the correlation between mouse and human pathogenesis.In summary, CMT2Z is known as an incurable genetic disorder, but the present study demonstrated its mechanisms and treatments based on established animal models. This study demonstrates that the Morc2a p.S87L variant causes hydroxyl radical-mediated neuropathy, which can be rescued through AAV-based gene therapy.

2024-06-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Corrigendum to “HSF1, in association with MORC2, downregulates ArgBP2 via the PRC2 family in gastric cancer cells” [Biochim. Biophys. Acta. Mol. Basis. Dis. 2018 Apr;1864(4 Pt A):1104–1114/PMID: 29339121]

作者: Li, Yan ; Liu, Funan ; Gu, Hui ; Tong, Yuxin ; Li, Feng ; Wang, Chunyu ; Shao, Yangguang

2024-03-01·Genes & diseases

Oncogenic MORC2 in cancer development and beyond.

Review

作者: Zhang, Shan ; Ren, Junyi ; Dong, Chenshuang ; Liu, Jia ; Wang, Guiling ; Wang, Huan ; Guo, Ayao

Microrchidia CW-type zinc finger 2 (MORC2) is a member of the MORC superfamily of nuclear proteins. Growing evidence has shown that MORC2 not only participates in gene transcription and chromatin remodeling but also plays a key in human disease and tumor development by regulating the expression of downstream oncogenes or tumor suppressors. The present review provides an updated overview of MORC2 in the aspect of cancer hallmark and therapeutic resistance and summarizes its upstream regulators and downstream target genes. This systematic review may provide a favorable theoretical basis for emerging players of MORC2 in tumor development and new insight into the potential clinical application of basic science discoveries in the future.

项与 MORC2 相关的新闻（医药）

2024-07-31

·今日头条

转移新机制！中国医科大学李丰团队：发现结肠癌治疗潜在靶点

本文为转化医学网原创，转载请注明出处作者：Jerry 导读：结直肠癌的发生和发展与异常的选择性剪接有关，但其分子机制仍未被充分探索。 7月24日，中国医科大学李丰研究团队在期刊《Cell Death&Disease》上发表了研究论文，题为“MORC2 regulates RBM39-mediated CDK5RAP2 alternative splicing to promote EMT and metastasis in colon cancer”，本研究中，研究人员发现CDK5RAP2 S促进结直肠癌细胞体外侵袭和体内转移。机制上，CDK5RAP2 S特异性地招募PHD指蛋白8，通过去除Slug启动子处的抑制性组蛋白标记来促进Slug的转录。此外，CDK5RAP2 S，而不是CDK5RAP2 L，在MORC2或RBM39诱导的上皮-间充质转化的促进必不可少。而且，MORC2, RBM39和Slug的高表达与结直肠癌患者的转移和不良临床结局密切相关。综上所述，本研究发现揭示了MORC2通过RBM39介导的pre-CDK5RAP2选择性剪接促进结直肠癌转移的新机制，并表明了MORC2/RBM39/CDK5RAP2轴作为结直肠癌的潜在治疗靶点。 https://www.nature.com/articles/s41419-024-06908-y#Sec11 背景知识 01 结直肠癌（CRC）是全球第三大诊断出的恶性疾病，也是癌症相关死亡的主要原因之一。除了基因突变外，异常的前体mRNA剪接已成为反映结直肠癌细胞异常的另一个主要事件。已证实剪接因子介导的替代剪接（AS）与结直肠癌进展密切相关。例如，SRSF6通过直接与ZO-1基因外显子23中的序列结合，调节ZO-1的异常剪接，从而促进结直肠癌进展。因此，进一步研究参与结直肠癌发生和发展的替代剪接事件及其相应的病理特征，有助于开发结直肠癌的生物标志物和治疗靶点。微小核体家族CW型锌指蛋白2（MORC2）是高度保守的MORC家族蛋白质的成员。它在表观遗传基因沉默、DNA修复、脂质生成和葡萄糖代谢中发挥着重要作用。研究发现，MORC2在多种癌症中上调表达，包括乳腺癌、胃癌、结直肠癌和肝癌。它促进癌细胞的生长、迁移、侵袭和转移。然而，MORC2对结肠癌中可变剪接的影响及其机制尚未被阐明。 RNA结合结构域蛋白39（RBM39）是一种参与转录共调控和前mRNA选择性剪接的RNA结合蛋白。多项转录组学研究也表明，RBM39调节多种基因的选择性剪接，其中包括与细胞周期相关的基因。RBM39介导的选择性剪接也与多种癌症的发生和发展有关，包括急性髓细胞白血病（AML）、乳腺癌、结直肠癌和肺癌。吲哚胺（E7070）是一种抗癌磺胺类化合物，可选择性招募RBM39至CUL4-DCAF15 E3泛素连接酶，并通过蛋白酶体降解对其进行降解，在小鼠模型中对神经母细胞瘤具有良好的疗效。然而，尚不清楚MORC2是否调节RBM39介导的选择性剪接在结肠癌中的作用。 CDK5RAP2 S在体外促进结肠癌细胞迁移和侵袭，在体内促进肿瘤转移 02 研究人员研究了两种CDK5RAP2亚型在结肠癌细胞中的分子功能。通过慢病毒感染SW480-luc细胞中CDK5RAP2敲低后过表达CDK5RAP2 L或CDK5RAP2 S，研究人员发现CDK5RAP2 S而非CDK5RAP2 L促进结肠癌细胞的迁移和侵袭。然后用蛋白质免疫印迹实验检测EMT标志物和几个重要的EMT转录因子的表达。结果表明，cdk5rap2l过表达上调钙黏蛋白E，下调神经钙粘素、波形蛋白、Slug和Twist1的表达。而过表达CDK5RAP2 S则下调钙黏蛋白E，上调神经钙粘素、波形蛋白、Zeb1、Slug和Twist1的表达，提示CDK5RAP2 L和CDK5RAP2 S在结肠癌细胞EMT中可能具有不同的作用。然后将四组SW480-luc细胞注射到裸鼠尾静脉，利用活体生物发光成像(BLI)检测CDK5RAP2 L或CDK5RAP2 S对肿瘤转移的影响。在注射癌细胞10分钟后，在小鼠肺中观察到等量的生物发光。每周对小鼠进行一次成像，结果显示，对照组和shCDK5RAP2 + CDK5RAP2 S组在注射后第3周开始发生转移，而此时shCDK5RAP2和shCDK5RAP2 + CDK5RAP2 L组未发现转移。在研究终点，与对照组相比，shCDK5RAP2和shCDK5RAP2 + CDK5RAP2 L组肺转移明显减少，而shCDK5RAP2 + CDK5RAP2 S组肺转移明显增加。肺组织荧光成像与肺组织HE染色结果一致。综上所述，这些发现表明CDK5RAP2 S在体内促进结肠癌细胞的转移。 MORC2和RBM39通过cdk5rap2s促进结肠癌细胞的EMT、迁移和侵袭 MORC2和RBM39通过CDK5RAP2 S促进结肠癌细胞的EMT、迁移和侵袭 03 MORC2通过调控EMT过程促进三阴性乳腺癌和胆管癌的转移。然而，RBM39在EMT过程中的作用尚不清楚。然后研究人员验证了MORC2和RBM39促进结肠癌细胞的EMT。此外，数据表明，CDK5RAP2 S过表达，而不是CDK5RAP2 L，部分恢复了由RBM39敲低或MORC2敲低引起的迁移和侵袭抑制作用。另外，研究人员发现过表达CDK5RAP2 S，而不是CDK5RAP2 L，逆转了RBM39敲低对钙黏蛋白E表达的促进作用，以及对神经钙粘素、波形蛋白、Zeb1、Slug和Twist1表达的抑制作用，并且使用胰岛素得到了一致的结果。而且，敲低MORC2也得到了类似的结果。综上所述，MORC2和RBM39通过CDK5RAP2 S促进结肠癌细胞的EMT，迁移和侵袭。 MORC2、RBM39和Slug蛋白高表达与结直肠癌转移相关 04 研究人员分析了MORC2和RBM39在结直肠癌患者中的表达。研究人员发现MORC2和RBM39的RNA和蛋白表达水平在队列的结直肠癌组织中显著升高。MORC2表达与肿瘤大小(p = 0.018)，临床分期(p = 0.003)，淋巴结转移(pN) (p = 0.010)和远处转移(pM) (p = 0.030)显著相关。同时，RBM39的表达与临床分期显著相关(p = 0.046)(表2)。研究人员还发现在结直肠癌组织中CDK5RAP2 L的表达降低，CDK5RAP2 S的表达升高。最后，对30例癌旁组织、60例原发癌无转移组织、40例原发癌伴淋巴结和远处转移组织连续切片进行免疫组织化学染色。结果表明，MORC2、RBM39和Slug在转移的结直肠癌组织中高表达，而钙黏蛋白E不表达或低表达。相关性分析显示，MORC2与RBM39、MORC2与Slug、RBM39与Slug在结直肠癌转移中表达呈正相关。同时，MORC2与钙黏蛋白E、RBM39与钙黏蛋白E、Slug与E-cadherin表达呈负相关。研究小结 05 综上所述，本研究结果揭示了MORC2通过与RBM39相互作用促进CDK5RAP2 L亚型向CDK5RAP2 S亚型转换从而促进结直肠癌发展的一种新机制。本研究结果不仅提供了一种新的机制，而且为结直肠癌的治疗提供了一种靶向MORC2/RBM39/CDK5RAP2轴的治疗策略。参考资料： https://www.nature.com/articles/s41419-024-06908-y#Sec11 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

信使RNA寡核苷酸