更新于：2024-09-19

SF3A2

更新于：2024-09-19

基本信息

别名

Prp11、PRPF11、SAP 62

+ [5]

简介

Involved in pre-mRNA splicing as a component of the splicing factor SF3A complex that contributes to the assembly of the 17S U2 snRNP, and the subsequent assembly of the pre-spliceosome 'E' complex and the pre-catalytic spliceosome 'A' complex (PubMed:10882114, PubMed:11533230). Involved in pre-mRNA splicing as a component of pre-catalytic spliceosome 'B' complexes, including the Bact complex (PubMed:29361316, PubMed:29360106, PubMed:30315277). Interacts directly with the duplex formed by U2 snRNA and the intron (PubMed:29360106).

关联

100 项与 SF3A2 相关的临床结果

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100 项与 SF3A2 相关的转化医学

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0 项与 SF3A2 相关的专利（医药）

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项与 SF3A2 相关的文献（医药）

2024-04-05·Science Advances

SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1

Article

作者: Liao, Li ; Ma, Xiao-Yan ; Andriani, Lisa ; Zhang, Fang-Lin ; Zhang, Yin-Ling ; Deng, Ling ; Ling, Yun-Xiao ; Hu, Shu-Yuan ; Li, Da-Qiang ; Yang, Shao-Ying ; Shao, Zhi-Ming

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 ( MKRN1 ) and promoting the expression of the dominant and oncogenic isoform, MKRN1-T1 . Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.

2024-04-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Identification of splicing factors signature predicting prognosis risk and the mechanistic roles of novel oncogenes in HNSCC

Article

作者: Li, Xiaojie ; Xu, Wei ; Zhao, Jinyao ; Qi, Yangfan ; Li, Huizheng ; Chen, Chaoqun ; Liu, Lin ; Wang, Yang ; Zhang, Jinrui ; Zhang, Wenjing ; Huang, Fang

Head and neck squamous cell carcinoma (HNSCC) is the most frequent subtype of head and neck cancer, generally with a poor prognosis and limited therapeutic options due to its highly heterogeneous malignancy. In this study, we screened functional splicing regulatory RNA binding proteins (RBPs) that were closely related with the prognosis of HNSCC patients and showed significant expression differences between HNSCC tumors and normal tissues. Based on this finding, we chose six candidate genes (HNRNPC, ZCRB1, RBM12B, SF3A2, SF3B3, and SRSF11) to generate a prognostic prediction model and validated the accuracy of the prognostic model for predicting patient survival outcomes. We found that the risk score predicted by our model can serve as an independent prognostic predictor. Notably, HNSCC tumors showing higher expression of SF3B3, HNRNPC, or ZCRB1 possessed higher risk scores in the discovered prediction model. The investigation of the underlying mechanism validated that knockdown of SF3B3, HNRNPC, and ZCRB1 separately induced a substantial impairment of HNSCC cell survival. Conversely, overexpression of each of the three genes promoted tumor cellular proliferation. High throughput RNA sequencing analysis revealed that changes in the expression of SF3B3 and HNRNPC remarkably affected alternative splicing of genes related to cell cycle regulation, whereas the depletion of ZCRB1 contributed to aberrant splicing events involving in DNA damage response. In addition, the prognostic prediction model's risk score was demonstrated to be related with the immune infiltration score. Particularly, SF3B3 has a negative correlation with CD8A expression. Therefore, our findings provide promising prognosis predictors and potential therapeutic targets for better treatment efficacy of HNSCC.

2023-12-01·Journal of Advanced Research

Ginsenoside Rb2 inhibits p300-mediated SF3A2 acetylation at lysine 10 to promote Fscn1 alternative splicing against myocardial ischemic/reperfusion injury

Article

作者: Guo, Chen ; Zhao, Daqing ; Lou, Jia ; Chen, Jinjin ; Tong, Xiaolin ; Yao, Yao ; Wang, Yisa ; Huang, Qingxia ; Zhao, Linhua ; Wu, Mingxia ; Li, Jing ; Yang, Wenzhi ; Li, Xiangyan

INTRODUCTIONGinsenosides (GS) derived from Panax ginseng can regulate protein acetylation to promote mitochondrial function for protecting cardiomyocytes. However, the potential mechanisms of GS for regulating acetylation modification are not yet clear.OBJECTIVESThis study aimed to explore the potential mechanisms of GS in regulating protein acetylation and identify ginsenoside monomer for fighting myocardial ischemia-related diseases.METHODSThe 4D-lable free acetylomic analysis was employed to gain the acetylated proteins regulated by GS pretreatment. The co-immunoprecipitation assay, immunofluorescent staining, and mitochondrial respiration measurement were performed to detect the effect of GS or ginsenoside monomer on acetylated protein level and mitochondrial function. RNA sequencing, site-specific mutation, and shRNA interference were used to explore the downstream targets of acetylation modificationby GS. Cellular thermal shift assay and surface plasmon resonance were used for identifying the binding of ginsenoside with target protein.RESULTSIn the cardiomyocytes of normal, oxygen glucose deprivation and/or reperfusion conditions, the acetylomic analysis identified that the acetylated levels of spliceosome proteins were inhibited by GS pretreatment and SF3A2 acetylation at lysine 10 (K10) was significantly decreased as a potential target of GS. Ginsenoside Rb2 was identified as one of the active ginsenoside monomers for reducing the acetylation of SF3A2 (K10), which enhanced mitochondrial respiration against myocardial ischemic injury in in vivo and in vitro experiments. RNA-seq analysis showed that ginsenoside Rb2 promoted alternative splicing of mitochondrial function-related genes and the level of fascin actin-bundling protein 1 (Fscn1) was obviously upregulated, which was dependent on SF3A2 acetylation. Critically, thermodynamic, kinetic and enzymatic experiments demonstrated that ginsenoside Rb2 directly interacted with p300 for inhibiting its activity.CONCLUSIONThese findings provide a novel mechanism underlying cardiomyocyte protection of ginsenoside Rb2 by inhibiting p300-mediated SF3A2 acteylation for promoting Fscn1 expression, which might be a promising approach for the prevention and treatment of myocardial ischemic diseases.

项与 SF3A2 相关的新闻（医药）

2024-04-09

·今日头条

再取进展！复旦大学李大强/邵志敏等合作揭示三阴性乳腺癌的潜在治疗新靶点

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：由于缺乏有效的治疗靶点，三阴性乳腺癌（TNBC）是最致命的乳腺癌亚型。 2024年4月3日，复旦大学李大强，邵志敏及 Fang-lin Zhang共同通讯在《Science Advances》上发表题为“SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alteRNAtive splicing of MKRN1”的研究论文，研究揭示了SF3A2在TNBC进展和顺铂耐药中以前未知的作用，突出了SF3A2作为TNBC患者的潜在治疗靶点。 https://www-science-org.libproxy1.nus.edu.sg/doi/10.1126/sciadv.adj4009 研究背景 01 乳腺癌（BC）是一种高度异质性的疾病，临床上根据雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）的表达状态进行分类，以指导治疗决策，从而大大改善BC患者的预后。然而，大约 15% 至 20% 的 BC（称为三阴性乳腺癌（TNBC））缺乏这些受体的表达，因此不能从内分泌和抗 HER2 治疗中获益，这进一步解释了与其他 BC 亚型相比， TNBC 的侵袭性更强、复发风险更高、预后更差。化疗仍然是TNBC患者全身治疗的主要手段。顺铂是一种DNA损伤剂，是目前最有效的化疗药物之一，广泛用于单独使用或与其他药物联合用于治疗TNBC。然而，相当一部分患者出现化疗耐药性，最终导致治疗失败，这是药物治疗的主要障碍。因此，确定针对TNBC进展和化疗耐药性的新治疗靶点是当务之急。研究进展 02 为了确定促进TNBC进展的潜在靶标，我们使用复旦大学上海肿瘤中心（FUSCC）-TNBC定量蛋白质组和RNA测序（RNA-seq）数据集分析了136个剪接因子的表达水平。根据log2FC（倍数变化）>1的筛选标准，与相邻正常组织相比，TNBC标本中有84个剪接因子在蛋白质水平失调，而64个剪接因子在mRNA水平失调（图1A）。其中，48个剪接因子在蛋白质和mRNA水平上均失调（图1，B和C，前30名）。我们选择SF3A2进行进一步研究，因为它在我们的筛选列表中排名靠前，而且在TNBC中的作用不明确。 SF3A2 在 TNBC 肿瘤中经常过表达，其高表达表明 TNBC 患者预后不良。在 FUSCC-TNBC 队列中，与正常乳腺组织相比，TNBC 组织中 SF3A2 的表达水平明显升高（图 1、D 和 E）。为了进一步验证这些结果，我们随后通过免疫印迹测定法检测了 20 对 TNBC 和正常组织中 SF3A2 的蛋白质水平。正如预期的那样，SF3A2在TNBC组织中的表达水平明显高于正常组织（图1，F和G）。此外，我们还分析了公开的CPTAC（临床蛋白质组学肿瘤分析联盟）和TCGA（癌症基因组图谱）数据集中SF3A2的表达水平。与 FUSCC-TNBC 队列的结果一致，与正常组织相比，SF3A2 在 BC 组织中明显过表达，在 TNBC 中的表达水平高于其他 BC 亚型。此外，Kaplan-Meier 分析表明，SF3A2 水平较高的患者在乳腺癌中的总生存期和无远处转移生存期较短。然而，值得注意的是，与所有乳腺癌患者相比，SF3A2 上调预测了 TNBC 患者的疾病预后更差（图 1H）。总的来说，这些结果表明 SF3A2 在 TNBC 样本中异常上调，其较高的表达预示着 TNBC 患者的预后较差。研究结果 03 在这项研究中，我们将 SF3A2 确定为 TNBC 中的一种癌蛋白，可作为 TNBC 患者的潜在治疗靶点。从机制上讲，UBR5 调节 SF3A2 的泛素化和降解。反过来，SF3A2正向调节UBR5的蛋白水平，从而形成调节这两种癌蛋白在TNBC中的表达水平的反馈回路。SF3A2 至少部分通过促进 MKRN1 剪接开关来促进 TNBC 进展。此外，SF3A2 耗竭通过 MKRN1-FADD 通路诱导外源性细胞凋亡，并通过 DNA 损伤触发内源性细胞凋亡，从而增强细胞对顺铂治疗的敏感性（图 7L）。总之，本研究描述了 SF3A2 在 TNBC 进展和顺铂耐药中以前未被识别的作用，表明SF3A2可能是TNBC的潜在治疗靶点。参考资料： https://www-cell-com.libproxy1.nus.edu.sg/cancer-cell/abstract/S1535-6108(24)00090-4#%20 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 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临床研究

2024-01-13

·生物探索

2024年，西湖大学施一公团队合作再取进展！

U2小核核糖核蛋白(snRNP)对pre-mRNA分支位点(BS)的选择对于剪接前体 (A complex)的组装至关重要。RNA解旋酶PRP5校对BS选择，但其潜在机制尚不清楚。2024年1月9日，西湖大学施一公及中国科学技术大学张晓峰共同通讯在Nature Structural & Molecular Biology 在线发表题为“Structural insights into branch site proofreading by human spliceosome”的研究论文，该研究报告了导致前质体组装的两个顺序复合物的原子结构:人类17S U2 snRNP和跨外显子pre-A复合物。PRP5主要通过酸性环占领SF3B1的RNA通路锚定在17S U2 snRNP上；PRP5的解旋酶结构域与U2 snRNA结合；U2 snRNA与BS相互作用的茎环(BSL)被TAT-SF1屏蔽，无法与BS接合。在pre-A配合物中，形成初始的U2-BS双相;PRP5的易位解旋酶结构域停留在U2 snRNA上，酸性环仍然占据RNA路径。pre-A构象被剪接因子SF1、DNAJC8和SF3A2特别稳定。癌症衍生的SF3B1突变破坏了其与PRP5的关联，损害了BS校对。总之，这些发现揭示了PRP5对剪接前体组装和BS选择或校对的关键见解。另外，2024年1月2日，上海科技大学刘如娟、西湖大学施一公及圣裘德儿童医院Xu Beisi等团队合作在Nucleic Acids Research 在线发表题为“THUMPD2 catalyzes the N2-methylation of U6 snRNA of the spliceosome catalytic center and regulates pre-mRNA splicing and retinal degeneration ”的研究论文，该研究发现一种RNA修饰-N2 -甲基鸟苷(m2G)沉积在U6 snRNA的G72上(剪接体的催化中心)，促进了人类细胞中有效的pre-mRNA剪接活性。这种修饰在脊椎动物中被证实是保守的。通过明确识别U6特异性序列和结构元件，THUMPD2被证明是负责U6 m2G72的甲基转移酶。敲除THUMPD2消除了U6 m2G72，破坏了pre-mRNA剪接活性，导致人类细胞中内源性pre-mRNA的数千个可选剪接事件发生变化。值得注意的是，异常剪接的pre-mRNA群体引发了无义介导的mRNA衰变途径。进一步表明，THUMPD2与年龄相关性黄斑变性和视网膜功能有关。因此，该研究证明了主要剪接体的RNA表观遗传修饰如何调节全局前mRNA剪接并影响生理和疾病。Pre-mRNA的剪接由剪接体执行，这是一种动态的超分子机器。剪接体通过识别内含子的保守元件:5 ' -剪接位点(5 'SS)、BS、聚嘧啶束(PPT)和3 ' -剪接位点(3 'SS)，组装在pre-mRNA上。首先，U1 snRNP、SF1、U2AF2和U2AF1分别识别5'SS、BS、PPT和3'SS，形成E complex。然后，U2 snRNP取代SF1，使U2 snRNA与BS之间形成双工，从而形成A complex。在高等真核生物中，大多数基因通过选择不同的剪接位点进行选择性剪接。因此，选择BS的A complex的形成是剪接调节的焦点。遗憾的是，人们对E-to-A转换背后的步骤知之甚少。RNA解旋酶PRP5(也称为DDX46)在A complex的组装过程中起关键作用。在人类17S U2 snRNP中，U2 snRNA无法与BS配对，因为U2 snRNA的相关序列形成双链BSL。ATP被PRP5水解导致BSL解绕，从而促进U2-BS双相的形成。在酵母中，Prp5可能校对U2-BS双工，因为Prp5突变允许使用隐性BS和3'SS。然而，PRP5调控剪接保真度的机制尚不清楚。17S人U2 snRNP和人pre-A剪接体的冷冻电镜结构（图源自Nature Structural & Molecular Biology ）大多数已知的癌症衍生的RNA剪接失调突变影响SF3B1的HEAT重复序列中的残基。这些突变大部分聚集在SF3B1的RNA通路上。Hsh155基因中的部分相应突变改变了Prp5相互作用和BS选择。尽管有这些诱人的线索，但这些癌症突变如何干扰正常剪接仍然是一个谜。该研究报道了人类17S U2 snRNP的高分辨率冷冻电镜(cryo-EM)结构和剪接抑制剂捕获的交叉外显子pre-A complex。结合结构导向的生化分析，该研究提出了一个校对BS选择和A complex组装的工作模型。总的来说，该研究为理解剪接体的早期组装过程以及分支位点的识别和选择机制提供了重要的结构信息，同时也为与癌症相关的SF3B1突变的致病机制提供了新的见解。参考文献：Zhang X, Zhan X, Bian T, Yang F, et al. Structural insights into branch site proofreading by human spliceosome. Nat Struct Mol Biol. 2024 Jan 9. doi: 10.1038/s41594-023-01188-0. Epub ahead of print. PMID: 38196034.责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

信使RNA