更新于：2024-09-19

FEN1

更新于：2024-09-19

基本信息

别名

DNase IV、FEN-1、FEN1

+ [6]

简介

Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structures that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.

关联

靶点

FEN1

作用机制

FEN1 抑制剂

在研机构

Nanyang Technological University

原研机构

Nanyang Technological University

在研适应症

肿瘤

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

FEN1(Seed Therapeutics)

靶点

FEN1

作用机制

FEN1 调节剂

在研机构

Seed Therapeutics, Inc.

原研机构

Seed Therapeutics, Inc.

在研适应症

肿瘤

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

BSM-1516

靶点

FEN1

作用机制

FEN1 抑制剂

在研机构

Blacksmith Medicines, Inc.初创企业

原研机构

Blacksmith Medicines, Inc.初创企业

在研适应症

肿瘤

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

100 项与 FEN1 相关的临床结果

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100 项与 FEN1 相关的转化医学

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0 项与 FEN1 相关的专利（医药）

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1,340

项与 FEN1 相关的文献（医药）

2024-12-31·Emerging Microbes & Infections

Evolutionary accumulation of FKS 1 mutations from clinical echinocandin-resistant Candida auris

Article

作者: Rong, Chen ; Zhang, Jingping ; Li, Hailong ; Wu, Yusheng ; Wu, Na ; Shang, Hong ; Jiang, Ning ; Tian, Sufei ; Chu, Yunzhuo

INTRODUCTIONDrug resistance to echinocandins, first-line drugs used to treat Candida auris infection, is rapidly emerging. However, the accumulation of mutations in genes other than FKS1 (before an isolate develops to resistance via FKS1 mutations), remains poorly understood. Methods: Four clinical cases and 29 isolates associated with the incremental process of echinocandin resistance were collected and analyzed using antifungal drug susceptibility testing and genome sequencing to assess the evolution of echinocandin resistance.FINDINGSSix echinocandin minimum inhibitory concentration (MIC)-elevated C. auris strains and seven resistant strains were isolated from the urinary system of patients receiving echinocandin treatment. Meanwhile, phylogenetic analyses illustrated that the echinocandin-resistant strains were closely related to other strains in the same patient. Genomic data revealed that the echinocandin-resistant strains had FKS1 mutations. Furthermore, three categories (ECN-S/E/R) of non-synonymous mutant SNP genes (such as RBR3, IFF6, MKC1, MPH1, RAD2, and MYO1) in C. auris appeared to be associated with the three-stage-evolutionary model of echinocandin resistance in C. glabrata: cell wall stress, drug adaptation, and genetic escape (FKS mutation).INTERPRETATIONEchinocandin-resistant C. auris undergoes spatial and temporal phase changes closely related to echinocandin exposure, particularly in the urinary system. These findings suggest that FKS1 mutations mediate an evolutionary accumulation of echinocandin resistance followed by modulation of chromosome remodelling and DNA repair processes that ultimately lead to FKS1 hot spot mutations and the development of drug resistance. This study provides an in-depth exploration of the molecular pathways involved in the evolution of Candida auris echinocandin resistance.

2024-12-01·Molecular Biology Reports

The endonuclease FEN1 mediates activation of STAT3 and facilitates proliferation and metastasis in breast cancer

Article

作者: Yu, Lin ; Wu, Benmeng ; Liu, Jingjing ; Huang, Xiaoshan ; Lan, Ting ; Zhu, Miaolin ; Wu, Min ; Zhu, Yaqin

BACKGROUNDThe metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis.METHODS AND RESULTSIn this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α).CONCLUSIONSThese results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.

2024-12-01·Clinical Proteomics

A reduced proteomic signature in critically ill Covid-19 patients determined with plasma antibody micro-array and machine learning

Article

作者: Patel, Maitray A ; Fraser, Douglas D ; Van Nynatten, Logan R ; Slessarev, Marat ; Daley, Mark ; Cepinskas, Gediminas

AbstractBackgroundCOVID-19 is a complex, multi-system disease with varying severity and symptoms. Identifying changes in critically ill COVID-19 patients’ proteomes enables a better understanding of markers associated with susceptibility, symptoms, and treatment. We performed plasma antibody microarray and machine learning analyses to identify novel proteins of COVID-19.MethodsA case-control study comparing the concentration of 2000 plasma proteins in age- and sex-matched COVID-19 inpatients, non-COVID-19 sepsis controls, and healthy control subjects. Machine learning was used to identify a unique proteome signature in COVID-19 patients. Protein expression was correlated with clinically relevant variables and analyzed for temporal changes over hospitalization days 1, 3, 7, and 10. Expert-curated protein expression information was analyzed with Natural language processing (NLP) to determine organ- and cell-specific expression.ResultsMachine learning identified a 28-protein model that accurately differentiated COVID-19 patients from ICU non-COVID-19 patients (accuracy = 0.89, AUC = 1.00, F1 = 0.89) and healthy controls (accuracy = 0.89, AUC = 1.00, F1 = 0.88). An optimal nine-protein model (PF4V1, NUCB1, CrkL, SerpinD1, Fen1, GATA-4, ProSAAS, PARK7, and NET1) maintained high classification ability. Specific proteins correlated with hemoglobin, coagulation factors, hypertension, and high-flow nasal cannula intervention (P < 0.01). Time-course analysis of the 28 leading proteins demonstrated no significant temporal changes within the COVID-19 cohort. NLP analysis identified multi-system expression of the key proteins, with the digestive and nervous systems being the leading systems.ConclusionsThe plasma proteome of critically ill COVID-19 patients was distinguishable from that of non-COVID-19 sepsis controls and healthy control subjects. The leading 28 proteins and their subset of 9 proteins yielded accurate classification models and are expressed in multiple organ systems. The identified COVID-19 proteomic signature helps elucidate COVID-19 pathophysiology and may guide future COVID-19 treatment development.

项与 FEN1 相关的新闻（医药）

2024-08-14

·微信

Sci Adv丨滞后链核小体组装和冈崎片段成熟的协同机制

引言真核生物的基因组DNA包裹在染色质中，因此真核DNA复制发生在染色质环境下。染色质的基本结构单位是核小体，由147 bp DNA缠绕的组蛋白八聚体组成，组蛋白多种翻译后修饰是表观遗传信息的承载基础。DNA复制时染色质打开然后重新建立，使得DNA复制和染色质复制的偶联，在此过程中亲本染色质携带的表观遗传信息被分配到新合成的子链DNA，因此染色质重建也是表观遗传信息继承的基础，维持基因组和表观基因组稳定。染色质重建的起始步骤是DNA复制偶联的核小体组装，同时也是表观遗传信息继承的关键一环，其核心是DNA合成和核小体组装的偶联。碱基配对形成了双螺旋结构的DNA，两条链的互补性决定了DNA是以半保留的方式进行复制。组成DNA的两条链是反向平行的，因此解螺旋的DNA的两条单链具有方向，一条是5’-3’，另一条链是3’-5’，但是DNA聚合酶都是5’-3’方向进行合成的，导致复制叉上两条链的合成方向相反。由此DNA复制的一条链是向复制叉前进的方向连续合成，称之为前导链，而另一条链的合成方向和复制叉前进的方向相反，先合成小片段DNA然后连接成完整的DNA分子，这个机制是冈崎夫妇发现的，所以这些短片段称之为冈崎片段，这条链称之为滞后链。滞后链冈崎片段合成先是Pol α合成带有一段RNA的DNA引物，然后发生聚合酶Pol α到 Pol δ的转换，Pol δ继续合成冈崎片段。其间Pol δ通过链置换反应入侵前一个冈崎片段，将含有RNA的保真度较低引物置换，形成单链翘起，进而招募Fen1等核酸酶进行切除被置换的单链DNA，产生的缺口被DNA连接酶（酵母中是Cdc9）连接，保障冈崎片段成熟，形成完整连续的滞后链DNA。伴随冈崎片段合成，核小体也会迅速组装，以免DNA暴露。前期Whitehouse和Smith的研究表明，真核生物的冈崎片段大小与核小体DNA和连接DNA的长度相当，且连接位置在核小体近中轴区，提出滞后链上核小体可以阻碍Pol δ的行进决定冈崎片段的长度【1, 2】。由于没有直接证据，核小体组装和冈崎片段成熟过程的协同机制尚不明确，李晴课题组发展了电镜核酸技术，对此机制进行了解析。 2024年8月9日，北京大学生命科学学院、北大-清华生命科学联合中心李晴课题组在Science Advances发表题为DNA polymerase δ subunit Pol32 binds histone H3-H4 and couples nucleosome assembly with Okazaki fragment processing的研究论文，巧妙利用DNA连接酶降解体系，应用电镜核酸技术观察酵母细胞中DNA复制叉中间体结构，发现核小体中组蛋白和DNA的相互作用决定了链置换的位置，而且DNA聚合酶δ的Pol32亚基在C端有一个组蛋白H3-H4的结合区域，可以直接贡献于后随链上的核小体组装，揭示了后随链上DNA合成和核小体组装的协同机制。研究者在芽殖酵母中利用AID（Auxin-induced degradation）系统诱导Cdc9在DNA复制早期快速降解，抑制冈崎片段末端的连接，进而在透射电镜下观察DNA复制中间体，发现在超过94%的复制叉上都含有翘起的DNA结构（flap structure），并且这个翘起结构主要集中在其中一条子链上，进一步的分析表明有翘起发生在滞后链 (图1)。通过测量翘起结构 (Flap) 的两个主要特征 (图2)：Flap本身的长度和相邻Flap的间距，研究者发现，1)在野生型背景下，Flap的长度集中分布在52 nt左右，其长度受到Pol δ的链置换活性和Fen1的核酸酶活性调控，而且Flap的长度分布具有13-15 nt的步长，可能是由核小体中周期性组蛋白和DNA相互作用障碍链置换合成造成的。2）相邻Flap的间距与冈崎片段长度相似，集中在190 bp左右。该间距的增大来自于DNA复制偶联的核小体组装突变，例如经典组蛋白分子伴侣CAF-1大亚基Cac1的缺失突变（cac1D）以及Mcm2结合组蛋白突变mcm2-3A，两个突变分别会导致新合成组蛋白的组装缺陷和旧组蛋白回收缺陷，这个间距增加到280bp左右，表明冈崎片段的合成受核小体组装程度调节。图1：电镜核酸技术观察DNA连接酶降解后的复制叉结构。图示复制泡结构；左图是Cdc9降解后，右图是未降解对照。（Credit: Science Advances）研究者在Pol δ亚基非催化亚基Pol32缺失突变中观察到flap间距变大，和上述提到核小体组装突变cac1D以及mcm2-3A的间距变化类似 (图2)。研究者进一步通过体内、体外分析直接证明了Pol32的C端可以直接结合组蛋白H3-H4，并通过ReIN-Map方法证明Pol32调节滞后链上的核小体组装。最近有两篇报道也分别揭示Pol32参与亲本组蛋白往后随链的递送，与我们的结论一致【3, 4】。图2：翘起结构 (Flap)的两个特征：Flap的长度 (A)和相邻Flap的间距(B)（Credit: Science Advances）综上，李晴课题组应用电镜核酸技术直接观察复制叉滞后链的分子事件，发现Pol32介导了核小体组装，进而提供了冈崎片段合成过程中链置换的终止位置，为冈崎片段成熟和核小体组装协同机制提供直接证据(图3)。图3：Pol32介导核小体组装与冈崎片段成熟协同机制。(i)　Pol δ催化冈崎片段合成；(ii)　冈崎片段合成后，通过Pol32快速组装H3-H4四聚体到新合成的DNA上；(iii)　Pol δ侵入先前产生的具有新生核小体的冈崎片段；(iv)　冈崎片段合成的重复循环，形成反应核小体间距的flap间距；在Pol32缺失突变体中，核小体组装水平下降导致核小体屏障的减少，进而导致冈崎片段增长。（Credit: Science Advances）参考文献 1. D. J. Smith, I. Whitehouse, Intrinsic coupling of lagging-strand synthesis to chromatin assembly. Nature 483, 434-U480 (2012). 2. N. C. Koussa, D. J. Smith, Post-replicative nick translation occurs on the lagging strand during prolonged depletion of DNA ligase I in. G3-Genes Genom Genet 11 (2021). 3. C. Tian et al., DNA polymerase delta governs parental histone transfer to DNA replication lagging strand. Proc Natl Acad Sci U S A 121, e2400610121 (2024). 4. A. Serra-Cardona et al., The PCNA–Pol δ complex couples lagging strand DNA synthesis to parental histone transfer for epigenetic inheritance. Science Advances 10, eadn5175 (2024). http://doi.org/10.1126/sciadv.ado1739 责编|探索君排版|探索君文章来源|“BioArt” 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 Cell | 是什么决定了细胞的大小？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

2024-08-07

·派真生物PackGene

Genome Biol丨中国药科大学徐澍等团队合作开发了一种新型RNA切割工具：TaqTth-hpRNA

致病性等位基因沉默是一种很有前途的治疗遗传性遗传病的方法。 2024年7月7日，中国药科大学徐澍、郭永健及司马健共同通讯在Genome Biology在线发表题为“TaqTth-hpRNA: a novel compact RNA-targeting tool for specific silencing of pathogenic mRNA”的研究论文，该研究开发了一种RNA切割工具：TaqTth-hpRNA，由一个小的嵌合TaqTth和一个发夹RNA引导探针组成。体外和体内研究表明，TaqTth-hpRNA具有最小的侧翼序列基序要求，可以有效和特异性地切割RNA。在阿尔茨海默病模型中，证明了在不改变野生型APP mRNA的情况下沉默突变APPswe mRNA。值得注意的是，由于TaqTth的紧凑大小，能够在单个AAV载体中与APOE2过表达结合，从而产生更强的病理抑制作用。多种RNA靶向策略的发现使高效的RNA编辑、RNA病毒抑制、核酸检测，当然还有基因治疗成为可能。基因治疗，特别是通过转录后RNA敲低介导的基因治疗，有可能成为治疗由致病性突变引起的疾病的理想方法。例如，在家族性阿尔茨海默病（FAD）中，致病性APP瑞典突变（APPswe）的等位基因特异性沉默导致过量的Aβ产生，是治疗FAD的一个有价值的武器。然而，考虑到野生型APP在中枢神经系统发育中起着至关重要的生理作用，野生型APP数量的脱靶改变（与突变致病APP在编码序列上只有一两个碱基差异）可能会加重AD症状。因此，应该探索更多的高特异性RNA敲低工具来区分靶标上的最小碱基差异。以前，报道过皮瓣内切酶1（FEN1）可以通过DNA探针而不是RNA探针来切割目标RNA。虽然可以区分目标底物“种子区”的单碱基差异，但效率有待进一步提高。与此同时，各种鲁棒性的RNA切割CRISPR效应物被开发出来，它们具有RNA引导的共同特征。虽然sgRNA作为质粒或PCR产物的DNA类型被转染到细胞中，但大量的转录产生是CRISPR系统高效的重要原因。与丰富的sgRNA相比，DNA探针在细胞核中自由扩散的数量是有限的。这启发在RNA探针的引导下探索高特异性RNA核酸酶。 TaqTth-hpRNA的设计和凝胶实验中的验证（图源自Genome Biology ）据报道，水热菌和嗜热菌DNA聚合酶（分别简称为TaqPol和TthPol）具有RNA依赖的5'核酸酶活性。此外，聚合酶家族包含与FEN1非常相似的功能域，推断聚合酶也可能像FEN1一样对靶底物的错配敏感。它也可能具有最小序列基序要求的优势，如fen1相关系统。因此，推测聚合酶可以识别RNA探针，并可以进一步设计为高效的RNA切割工具。在这项研究中，新的RNA切割工具将在体外和体内进行构建和测试，包括效率、特异性、序列-基序要求和细胞毒性。然后，将应用它来证明对APPswe突变的强敲除，避免改变野生型APP mRNA。考虑到TaqTth的紧凑大小，将尝试将其与人载脂蛋白E2（APOE2）过表达编码在单一AAV载体中结合，以抑制小鼠模型的病理变化。因此，相信这个新的工具包，作为现有系统的替代方案，可能有潜力为基因治疗策略提供宝贵的工具。 TaqTth的大小紧凑，能在单个AAV载体中与APOE2过表达结合从而产生更强的病理抑制作用。派真生物一站式CRO&CDMO服务平台，可提供全面的病毒载体包装服务和个性化定制服务。我们的产品线涵盖腺相关病毒(AAV)载体、慢病毒载体、mRNA服务，为您的遗传性遗传病基因治疗研究提供全方位的支持，欢迎后台留言咨询详情。转自：iNature 关于派真生物

基因疗法信使RNA

2024-05-23

·GlobeNewswire-Health Care

Brain Cancer Canada Awards an $80,000 research grant to the development of dual function therapies that harness the body's own immune system to kill brain tumour cells in glioblastomas

TORONTO, May 23, 2024 (GLOBE NEWSWIRE) -- Brain Cancer Canada is excited to announce $80,000 research grant has been awarded to Dr. Peter Stirling, PhD, Associate Professor at the University of British Columbia and Senior Scientist at the Terry Fox Laboratory, BC Cancer. This grant supports innovative research aimed at developing bi-functional FEN1 inhibitors that promise to enhance the treatment of glioblastomas by inducing synthetic lethality and stimulating the immune response within tumors. Dr. Stirling's project, titled "Developing new dual function therapies that kill tumour cells and activate immune responses in glioblastomas," targets the aggressive and notoriously treatment-resistant glioblastoma (GBM) tumors. These tumors often suppress local immune responses, making them difficult to treat with conventional chemotherapy alone. The research focuses on a novel chemotherapeutic approach that not only targets tumor cells but also activates the local immune system, potentially overcoming the immune resistance often seen in glioblastomas. The project benefits from the collaboration with experts like Dr. Philip Hieter and Dr. Sheila Singh, who bring specialized knowledge in molecular genetics and clinical practice, respectively. This diverse team will develop therapies that are expected to attack glioblastomas on two fronts: directly killing sensitive tumor cells and recruiting the immune system to tackle resistant cells. Dr. Stirling shared his vision for the project, stating, "Our goal is to transform the treatment landscape for glioblastoma patients by developing therapies that are not only more effective but also harness the body's own immune system to fight cancer. This could significantly improve outcomes for patients facing this challenging diagnosis." Anita Angelini, Vice Chair of Brain Cancer Canada, highlighted the significance of the community and corporate support: "This research is made possible through the generous contributions from Hudson Insurance Group, alongside our dedicated corporate and personal donors. Their support is crucial in bridging the gap between innovative research and tangible treatment advancements." The research integrates cutting-edge technology with clinical insights to address the complex nature of glioblastoma. By focusing on the DNA damage response and its interaction with immune system activation, Dr. Stirling's team is paving the way for novel therapeutic strategies that could substantially impact glioblastoma treatment protocols. This grant follows two other significant research grants issued by Brain Cancer Canada this month, supporting projects led by Dr. Claire Dubois at the Université de Sherbrooke and Dr. Sujoy Banik at London Health Sciences Centre and the Lawson Health Research Institute. Each of these grants is part of Brain Cancer Canada's broader initiative during May's Brain Cancer Awareness Month, known as 'Go Grey in May.' These efforts collectively demonstrate our commitment to advancing research and support for brain cancer patients across Canada. For more details about this ground-breaking research initiative and other efforts by Brain Cancer Canada, please contact sac@braincancercanada.ca Brain Cancer Canada is a national charity dedicated to supporting individuals diagnosed with malignant brain tumors. Through funding innovative research, neurosurgical technology, and advocating for increased options for treatments, Brain Cancer Canada aims to improve survival rates and the quality of life for patients, while providing essential support to their families. Media Contact: Media@braincancercanada.ca