更新于：2024-05-01

CPSF3

cleavage and polyadenylation specific factor 3

更新于：2024-05-01

基本信息

别名

cleavage and polyadenylation specific factor 3、Cleavage and polyadenylation specificity factor 73 kDa subunit、Cleavage and polyadenylation specificity factor subunit 3

+ [6]

简介

Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Has endonuclease activity, and functions as mRNA 3'-end-processing endonuclease (PubMed:30507380). Also involved in the histone 3'-end pre-mRNA processing (PubMed:30507380). U7 snRNP-dependent protein that induces both the 3'-endoribonucleolytic cleavage of histone pre-mRNAs and acts as a 5' to 3' exonuclease for degrading the subsequent downstream cleavage product (DCP) of mature histone mRNAs. Cleavage occurs after the 5'-ACCCA-3' sequence in the histone pre-mRNA leaving a 3'hydroxyl group on the upstream fragment containing the stem loop (SL) and 5' phosphate on the downstream cleavage product (DCP) starting with CU nucleotides. The U7-dependent 5' to 3' exonuclease activity is processive and degrades the DCP RNA substrate even after complete removal of the U7-binding site. Binds to the downstream cleavage product (DCP) of histone pre-mRNAs and the cleaved DCP RNA substrate in a U7 snRNP dependent manner. Required for entering/progressing through S-phase of the cell cycle (PubMed:30507380). Required for the selective processing of microRNAs (miRNAs) during embryonic stem cell differentiation via its interaction with ISY1 (By similarity). Required for the biogenesis of all miRNAs from the pri-miR-17-92 primary transcript except miR-92a (By similarity). Only required for the biogenesis of miR-290 and miR-96 from the pri-miR-290-295 and pri-miR-96-183 primary transcripts, respectively (By similarity).

关联

项与 CPSF3 相关的药物

AN-15368

靶点-

作用机制

CPSF3抑制剂

在研机构

Anacor Pharmaceuticals LLC

原研机构

Anacor Pharmaceuticals LLC

在研适应症

Chagas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

JTE-607

靶点

CPSF3

作用机制

CPSF3抑制剂

在研机构-

原研机构

日本烟草（香港）有限公司

在研适应症-

非在研适应症

全身炎症反应综合征

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CPSF3 相关的临床结果

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100 项与 CPSF3 相关的转化医学

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0 项与 CPSF3 相关的专利（医药）

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125

项与 CPSF3 相关的文献（医药）

2024-01-08·RNA (New York, N.Y.)

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing.

Article

作者: Abdulrahman A Alahmari ; Aditi H Chaubey ; Venkata S Jonnakuti ; Arwen A Tisdale ; Carla D Schwarz ; Abigail C Cornwell ; Kathryn E Maraszek ; Emily J Paterson ; Minsuh Kim ; Swati Venkat ; Eduardo Cortes Gomez ; Jianmin Wang ; Katerina V Gurova ; Hari Krishna Yalamanchili ; Michael E Feigin

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target Cleavage and Polyadenylation Specificity Factor 3 (CPSF3), the 3' endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of non-transformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional read-through in replication-dependent histones, reduces core histone expression, destabilizes chromatin structure and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.

2024-01-01·PeerJ

Identification of a necroptosis-related gene signature for making clinical predictions of the survival of patients with lung adenocarcinoma.

Article

作者: Xiaoping Zhou ; Ming Zhao ; Yingzi Fan ; Ying Xu

Background:

Lung adenocarcinoma (LUAD) is a major pathological subtype of malignant lung cancer with a poor prognosis. Necroptosis is a caspase-independent programmed cell death mode that plays a pivotal role in cancer oncogenesis and metastasis. Here, we explore the prognostic values of different necroptosis-related genes (NRGs) in LUAD.

Methods:

mRNA expression data and related clinical information for LUAD samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. NRGs were identified using the GeneCards database. Least absolute shrinkage and selection operator Cox regression and multivariate Cox analysis were used to construct a prognostic risk model. Time-dependent receiver-operating characteristic curves and a nomogram were constructed to validate the predictive values of the prognostic signatures. A necroptosis-related protein-protein interaction network was visualised using the STRING database and Cytoscape software. Functional analyses, including Gene Ontology, Kyoto Encyclopaedia of Genes and Genomes pathway enrichment, gene set enrichment, and gene set variation analyses, were conducted to explore the underlying molecular mechanisms. Finally, the mRNA expression of the prognostic signatures in LUAD cell lines was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis.

Results:

A prognostic model was established for eight NRGs (CALM1, DDX17, FPR1, OGT, PGLYRP1, PRDX1, TUFM, and CPSF3) based on TCGA-cohort data and validated with the GSE68465 cohort. Patients with low-risk scores had better survival outcomes than those with high-risk scores (p = 0.00013). The nomogram was used to predict the prognosis of patients with LUAD. The prediction curves for 1-, 3-, and 5-year OS showed good predictive performance and the accuracy of the nomograms increased over time. RT-qPCR results demonstrated that these eight genes, especially CALM1, PRDX1, and PGLYRP1, were differentially expressed in LUAD cells.

Conclusion:

We constructed a reliable eight-NRG signature that provides new insights for guiding clinical practice in the prognosis and treatment of LUAD.

2023-11-24·Science advances

Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer.

Article

作者: Peiye Shen ; Kaiyan Ye ; Huaijiang Xiang ; Zhenfeng Zhang ; Qinyang He ; Xiao Zhang ; Mei-Chun Cai ; Junfei Chen ; Yunheng Sun ; Lifeng Lin ; Chunting Qi ; Meiying Zhang ; Lydia W T Cheung ; Tingyan Shi ; Xia Yin ; Ying Li ; Wen Di ; Rongyu Zang ; Li Tan ; Guanglei Zhuang

Transcriptional dysregulation is a recurring pathogenic hallmark and an emerging therapeutic vulnerability in ovarian cancer. Here, we demonstrated that ovarian cancer exhibited a unique dependency on the regulatory machinery of transcriptional termination, particularly, cleavage and polyadenylation specificity factor (CPSF) complex. Genetic abrogation of multiple CPSF subunits substantially hampered neoplastic cell viability, and we presented evidence that their indispensable roles converged on the endonuclease CPSF3. Mechanistically, CPSF perturbation resulted in lengthened 3'-untranslated regions, diminished intronic polyadenylation and widespread transcriptional readthrough, and consequently suppressed oncogenic pathways. Furthermore, we reported the development of specific CPSF3 inhibitors building upon the benzoxaborole scaffold, which exerted potent antitumor activity. Notably, CPSF3 blockade effectively exacerbated genomic instability by down-regulating DNA damage repair genes and thus acted in synergy with poly(adenosine 5'-diphosphate-ribose) polymerase inhibition. These findings establish CPSF3-dependent transcriptional termination as an exploitable driving mechanism of ovarian cancer and provide a promising class of boron-containing compounds for targeting transcription-addicted human malignancies.

项与 CPSF3 相关的新闻（医药）

2024-03-22

·生物探索

Cell Discov | 西湖大学谢琦等团队揭示胶质母细胞瘤干细胞的选择性聚腺苷化

引言胶质母细胞瘤是最致命的恶性肿瘤之一，表现出明显的肿瘤内异质性，其中胶质母细胞瘤干细胞（GSCs）对肿瘤发生和治疗抵抗起着重要作用。泛素连接酶和去泛素化酶的药物调节剂正在开发用于癌症和其他疾病。2024年3月19日，西湖大学谢琦，深圳湾实验室李磊和匹兹堡大学Jeremy N. Rich共同通讯在Cell Discovery 发表题为“RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation”的研究论文。该研究进行了并行的体外和体内CRISPR/Cas9敲除筛选，针对人类泛素E3连接酶和去泛素化酶，揭示了E3连接酶RBBP6作为GSC维持的一个必需因子，靶向RBBP6抑制了GSC的增殖和肿瘤起始。在机制上，RBBP6介导CPSF3的K63-链接泛素化，稳定了CPSF3来调节选择性多腺苷酸化事件。RBBP6敲除导致MYC竞争性内源性RNA的3'UTR缩短，从而释放了miR-590-3p从缩短的UTRs中，从而降低了MYC的表达。用小分子抑制剂（JTE-607）靶向CPSF3可以减少GSC的存活率并抑制体内肿瘤生长。总的来说，RBBP6通过调节CPSF3依赖的选择性多腺苷酸化在GSC中维持高MYC表达，为胶质母细胞瘤提供了一个潜在的治疗范例。胶质母细胞瘤是最常见和致命的原发性脑肿瘤，中位生存时间不到两年。目前胶质母细胞瘤的标准治疗包括最大程度的手术切除，联合放疗和化疗，随后进行辅助化疗，只能提供姑息治疗。胶质母细胞瘤表现出肿瘤内异质性，其中自我更新的胶质母细胞处于层级顶端。胶质母细胞以其自我更新和肿瘤起始能力而功能特异化，此外还对肿瘤血管生成、放射抵抗力和化疗抵抗力有额外的贡献。胶质母细胞瘤是最早进行全面遗传分析的肿瘤之一，揭示了导致信号传导失调的频繁变异，包括涉及表观遗传学变化、转录调节因子和转录后调节的变异。然而，基于遗传突变的精准医学对胶质母细胞瘤患者的临床管理影响有限，表明替代的分子靶点可能提供治疗益处。泛素化是调节底物蛋白命运和/或功能的最常见的翻译后修饰之一。泛素-蛋白酶体通路维持大多数蛋白质的稳态。泛素分子通过涉及E1（泛素激活）、E2（泛素连接）和E3（泛素连接酶）酶的催化级联添加到靶标蛋白中，可以通过去泛素化酶（DUBs）逆转。先前的研究已将泛素途径与胶质母细胞瘤的生长总体和GSC的维持特异性联系起来。例如，胶质母细胞瘤可能过表达USP15，该酶结合SMAD7-SMAD特异性E3泛素蛋白连接酶2（SMURF2）复合物去泛素化并稳定型I转化生长因子-β受体（TβR-I），增强TGF-β信号传导。在GSCs中，USP9x取消乙醛脱氢酶1A3（ALDH1A3）的多泛素化以稳定ALDH1A3并维持GSCs。用USP9x抑制剂WP1130处理GSCs可诱导ALDH1A3降解并抑制GSC的生长。此外，USP13和FBXL14相互调节GSCs中MYC的多泛素化。因此，去泛素化酶和泛素连接酶可能是胶质母细胞瘤的潜在治疗靶点。模式图（Credit: Cell Discovery）CRISPR/Cas9基因敲除（KO）高通量筛选已被证明是癌症治疗中目标基因发现的有效平台。先前的CRISPR筛选研究主要集中在体外培养的细胞模型上，这些模型无法充分代表肿瘤微环境的复杂效应，这种方法可能限制了药物开发的成功。在这里，作者改进了一种更具生理学相关性的体内CRISPR筛选方法，以识别对GSC维持和肿瘤形成至关重要的泛素连接酶和去泛素化酶。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1038/s41421-024-00654-3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

临床1期蛋白降解靶向嵌合体