更新于：2024-09-19

MMS19

更新于：2024-09-19

基本信息

别名

CIAO4、hMMS19、MET18

+ [6]

简介

Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into apoproteins specifically involved in DNA metabolism and genomic integrity (PubMed:29848660). In the CIA complex, MMS19 acts as an adapter between early-acting CIA components and a subset of cellular target iron-sulfur proteins such as ERCC2/XPD, FANCJ and RTEL1, thereby playing a key role in nucleotide excision repair (NER), homologous recombination-mediated double-strand break DNA repair, DNA replication and RNA polymerase II (POL II) transcription (PubMed:22678362, PubMed:22678361, PubMed:29225034, PubMed:23585563). As part of the mitotic spindle-associated MMXD complex, plays a role in chromosome segregation, probably by facilitating iron-sulfur (Fe-S) cluster assembly into ERCC2/XPD (PubMed:20797633). Together with CIAO2, facilitates the transfer of Fe-S clusters to the motor protein KIF4A, which ensures proper localization of KIF4A to mitotic machinery components to promote the progression of mitosis (PubMed:29848660). Indirectly acts as a transcriptional coactivator of estrogen receptor (ER), via its role in iron-sulfur insertion into some component of the TFIIH-machinery (PubMed:11279242).

关联

100 项与 MMS19 相关的临床结果

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100 项与 MMS19 相关的转化医学

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0 项与 MMS19 相关的专利（医药）

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项与 MMS19 相关的文献（医药）

2024-06-17·Journal of Clinical Investigation

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes

Article

作者: Straub, Volker ; Muntoni, Francesco ; Zaharieva, Irina T ; Pais, Lynn ; Silverstein, Sarah ; Sewry, Caroline ; Sarkozy, Anna ; Hu, Ying ; Orbach, Rotem ; Sudhakar, Sniya ; Verma, Sumit ; Peric, Stojan ; Willis, Tracey ; Mueller, Juliane ; DiTroia, Stephanie ; Donkervoort, Sandra ; Maio, Nunziata ; Bönnemann, Carsten G ; Foley, A Reghan ; Munot, Pinki ; Töpf, Ana ; Douglas, Ganka ; Rouault, Tracey A ; Grunseich, Christopher ; Krishnakumar, Deepa

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.

2024-06-01·Genetics in Medicine

CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders

作者: Moeschler, John B ; van der Wel, Nicole N ; Ban, Kevin ; Grootemaat, Anita E ; Schomakers, Bauke V ; Leen, René ; Dobritzsch, Doreen ; Labrune, Philippe ; van Klinken, Jan B ; Roseboom, Winfried ; Filiano, James J ; Kochan, Jakub ; Dyment, David ; van Karnebeek, Clara D M ; Berman, Jason N ; van der Lee, Robin ; Ross, Colin J ; Pena, Izabella A ; Drögemöller, Britt I ; Kramer, Gertjan ; Correard, Solenne ; Pras-Raves, Mia L ; Jaspers, Yorrick R J ; Weschke, Bernhard ; Meinsma, Rutger ; Roelofsen, Jeroen ; McIntyre, Rebecca L ; Tarailo-Graovac, Maja ; Ferreira, Carlos R ; van Kuilenburg, André B P ; Zoetekouw, Lida ; Wasserman, Wyeth W ; Prykhozhij, Sergey V ; Garavaglia, Barbara ; Schock, Sarah ; Ekker, Marc ; van Weeghel, Michel ; Willemsen, Michèl A ; Riva, Daria ; Houtkooper, Riekelt H ; Saxena, Vishal ; Vaz, Frédéric M ; Jansen-Meijer, Judith

PURPOSEThe functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.METHODSGenetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences.RESULTSMetabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models.CONCLUSIONA general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.

2024-03-20·Science Translational Medicine1区 · 医学

Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly

1区 · 医学

Article

作者: Ye, Dan ; Rich, Jeremy N ; Ji, Jing ; Shi, Zhumei ; You, Yongping ; Ge, Zehe ; Liu, Wentao ; Zhou, Qigang ; Wang, Xiuxing ; Lin, Fan ; He, Liuguijie ; Zhao, Ningwei ; Ge, Xin ; Shu, Chuanjun ; Qian, Xu ; Yin, Jianxing ; Wang, Xiefeng ; Cao, Yuandong ; Zhang, Junxia ; Wang, Qianghu ; Song, Keying ; Ding, Fangshu

Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration–approved prescription drug N -acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery–mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.

项与 MMS19 相关的新闻（医药）

2024-03-22

·生物探索

Sci Transl Med | 南京医科大学钱旭/尤永平/汪秀星揭示抑制胞质铁硫组装可重新激活PTEN损害胶质瘤干细胞

引言胶质母细胞瘤是最致命的原发性脑肿瘤，携带着能够启动和维持恶性表型并增强治疗抵抗力的胶质母细胞（GSCs）。尽管PTEN在胶质母细胞瘤中经常发生突变，但PTEN在PTEN完整的GSCs中的功能和调控尚不清楚。2024年3月20日，南京医科大学钱旭，尤永平和汪秀星共同通讯在Science Translational Medicine在线发表题为“Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly”的研究论文，该研究发现PTEN直接与MMS19相互作用，并竞争性地破坏分化的胶质瘤细胞中基于MMS19的细胞质铁硫（Fe-S）簇装配（CIA）机制。与匹配的分化的胶质瘤细胞相比，PTEN在GSCs中的胱氨酸（C）211位点特异性地发生琥珀酸化。同位素示踪结合质谱分析证实，由于在GSCs中高度活化的新生嘌呤合成途径中由腺苷琥珀酸合酶（ADSL）产生的富马酸促进了PTEN C211的琥珀酸化。这种修饰取消了PTEN与MMS19之间的相互作用，重新激活了GSCs中的CIA机制途径。在功能上，通过重新表达PTEN C211S突变体，通过shRNA去除ADSL，或通过美国食品药品监督管理局批准的处方药乙酰半胱氨酸（NAC）消耗富马酸，抑制了GSC的维持。通过重新表达PTEN C211S或使用NAC治疗使GSC源性脑肿瘤对于替莫唑胺和放射疗法，即胶质母细胞瘤患者的标准治疗，产生了敏感性，通过减缓CIA机械介导的DNA损伤修复。这些发现揭示了一种立即可行的策略，通过重组NAC的联合治疗来靶向GSCs治疗胶质母细胞瘤。胶质母细胞瘤（GBM）是最常见和最恶性的原发性脑肿瘤。目前的治疗方案是最大限度地切除手术，随后进行同时化疗和放疗以及辅助化疗，但只能提供缓解治疗，从诊断时间算起，患者的中位总生存期不到15个月。GBM含有由胶质母细胞（GSCs）强化的多种细胞群的细胞层级结构，这些细胞群在功能上通过广泛的自我更新和多线分化来定义。GSCs在体内形成的肿瘤与患者肿瘤相似，使它们成为脑肿瘤研究的良好模型。GSCs对传统化疗和放疗的抵抗与非干细胞或分化的胶质细胞（DGCs）相比也支持了它们在临床上的重要性。利用GSCs的调节可能为改善GBM患者的临床结果提供关键信息。PTEN是一个众所周知的肿瘤抑制基因，它转移到细胞膜上，在那里通过去磷酸化和抑制磷脂酰肌醇3-激酶（PI3K）信号来抑制磷脂酰肌醇（3,4,5）-三磷酸（PIP3）依赖性过程，如AKT的膜招募和活化。我们最近报告了PTEN的琥珀酸化，这是PTEN的最近鉴定的翻译后修饰之一，阻碍了它在细胞膜上的定位，从而减弱了它对PI3K/AKT途径的抑制作用。除了通过其脂质磷酸酶活性对PI3K/AKT的抑制作用外，我们报道了PTEN作为蛋白质磷酸酶的功能，它去磷酸化磷酸化的磷酸甘油酸激酶1（PGK1），抑制了PGK1的糖酵解酶活性，从而抑制了糖酵解和脑肿瘤的生长。除了其脂质和蛋白质磷酸酶活性外，PTEN作为一个复合调节因子，展示了复杂的机制，包括调节染色质稳定性、DNA损伤修复和基因转录。尽管在GBMs中经常发生突变，但在大量GSCs中发现PTEN是完整的。然而，PTEN在GSCs中的调节和临床意义尚未明确定义。优先吸收铁是GSCs的特点之一。铁硫（Fe-S）簇是许多参与基本生物过程的蛋白质的无机辅因子。生成这些簇需要线粒体Fe-S组装机和细胞质铁硫（Fe-S）簇组装（CIA）机的成员之间的协调活动。后一条途径充当一个通道，其中Fe-S含量的辅因子从线粒体Fe-S组装中生成，并通过一系列蛋白质最终被结合到调控细胞周期或DNA复制和修复的细胞质或核蛋白中。这个过程的一个关键终端适配器是MMS19同源物，它与许多重要的DNA代谢和DNA损伤修复相关的蛋白质结合。已经鉴定了CIA机械途径中的核心组装蛋白和特定的Fe-S靶向蛋白。然而，CIA机械途径的调节仍然是一个巨大的空白。PTEN在C211位点的琥珀化对GSC的维持至关重要（Credit: Science Translational Medicine）该研究证明PTEN直接与MMS19相互作用，并竞争性地干扰了依赖于MMS19的CIA机械。在GSCs中高度活跃的嘌呤合成途径为PTEN在C211位点（PTEN C211sc）的琥珀酸化提供了丙二酸，这消除了PTEN与MMS19之间的相互作用，从而减轻了PTEN对CIA机械的抑制作用，促进了GSC的维持和脑肿瘤发生。原文链接https://www-science-org.libproxy1.nus.edu.sg/doi/10.1126/scitranslmed.adg5553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Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文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

放射疗法