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Design principles and applications of synthetic self-replicating RNAs. 合成自我复制rna的设计原理和应用。
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-06-01 DOI: 10.1002/wrna.1803
Alexander Wagner, Hannes Mutschler

With the advent of ever more sophisticated methods for the in vitro synthesis and the in vivo delivery of RNAs, synthetic mRNAs have gained substantial interest both for medical applications, as well as for biotechnology. However, in most biological systems exogeneous mRNAs possess only a limited half-life, especially in fast dividing cells. In contrast, viral RNAs can extend their lifetime by actively replicating inside their host. As such they may serve as scaffolds for the design of synthetic self-replicating RNAs (srRNA), which can be used to increase both the half-life and intracellular concentration of coding RNAs. Synthetic srRNAs may be used to enhance recombinant protein expression or induce the reprogramming of differentiated cells into pluripotent stem cells but also to create cell-free systems for research based on experimental evolution. In this article, we discuss the applications and design principles of srRNAs used for cellular reprogramming, mRNA-based vaccines and tools for synthetic biology. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution.

随着越来越复杂的rna体外合成和体内递送方法的出现,合成mrna在医学应用和生物技术方面都获得了极大的兴趣。然而,在大多数生物系统中,外源性mrna只有有限的半衰期,特别是在快速分裂的细胞中。相比之下,病毒rna可以通过在宿主体内积极复制来延长它们的寿命。因此,它们可以作为设计合成自复制rna (srRNA)的支架,可用于增加编码rna的半衰期和细胞内浓度。合成srRNAs可用于增强重组蛋白表达或诱导分化细胞重编程为多能干细胞,也可用于基于实验进化的研究创建无细胞系统。在本文中,我们讨论了srrna用于细胞重编程、基于mrna的疫苗和合成生物学工具的应用和设计原则。本文分类为:疾病与发展中的RNA;疾病与发展中的RNA;疾病与发展中的RNA; bb1发育中的RNA; RNA进化与基因组学;bb2 RNA与核糖核蛋白进化。
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引用次数: 0
tRNA-derived RNAs: Biogenesis and roles in translational control. trna衍生的rna:生物发生及其在翻译控制中的作用。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-07-05 DOI: 10.1002/wrna.1805
Yasutoshi Akiyama, Pavel Ivanov

Transfer RNA (tRNA)-derived RNAs (tDRs) are a class of small non-coding RNAs that play important roles in different aspects of gene expression. These ubiquitous and heterogenous RNAs, which vary across different species and cell types, are proposed to regulate various biological processes. In this review, we will discuss aspects of their biogenesis, and specifically, their contribution into translational control. We will summarize diverse roles of tDRs and the molecular mechanisms underlying their functions in the regulation of protein synthesis and their impact on related events such as stress-induced translational reprogramming. This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.

tRNA衍生RNA (Transfer RNA -derived RNAs, tDRs)是一类小分子非编码RNA,在基因表达的不同方面发挥重要作用。这些普遍存在的异质rna在不同的物种和细胞类型中存在差异,被认为可以调节各种生物过程。在这篇综述中,我们将讨论它们的生物发生方面,特别是它们在翻译控制中的贡献。我们将总结tdr的不同作用及其在蛋白质合成调控中的分子机制,以及它们对应激诱导的翻译重编程等相关事件的影响。本文分为:RNA加工>小RNA加工调控RNA /RNAi/Riboswitches >调控RNA调控RNA /RNAi/Riboswitches >效应小RNA的生物发生。
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引用次数: 0
Undervalued and novel roles of heterogeneous nuclear ribonucleoproteins in autoimmune diseases: Resurgence as potential biomarkers and targets. 异质核核糖核蛋白在自身免疫性疾病中被低估的新作用:作为潜在生物标志物和靶标的复兴
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-06-26 DOI: 10.1002/wrna.1806
Kangzhi Chen, Mengchuan Luo, Yuanzhi Lv, Zhaohui Luo, Huan Yang

Autoimmune diseases are mainly characterized by the abnormal autoreactivity due to the loss of tolerance to specific autoantigens, though multiple pathways associated with the homeostasis of immune responses are involved in initiating or aggravating the conditions. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a major category of RNA-binding proteins ubiquitously expressed in a multitude of cells and have attracted great attentions especially with their distinctive roles in nucleic acid metabolisms and the pathogenesis in diseases like neurodegenerative disorders and cancers. Nevertheless, the interplay between hnRNPs and autoimmune disorders has not been fully elucidated. Virtually various family members of hnRNPs are increasingly identified as immune players and are pertinent to all kinds of immune-related processes including immune system development and innate or adaptive immune responses. Specifically, hnRNPs have been extensively recognized as autoantigens within and even beyond a myriad of autoimmune diseases, yet their diagnostic and prognostic values are seemingly underestimated. Molecular mimicry, epitope spreading and bystander activation may represent major putative mechanisms underlying the presence of autoantibodies to hnRNPs. Besides, hnRNPs play critical parts in regulating linchpin genes expressions that control genetic susceptibility, disease-linked functional pathways, or immune responses by interacting with other components particularly like microRNAs and long non-coding RNAs, thereby contributing to inflammation and autoimmunity as well as specific disease phenotypes. Therefore, comprehensive unraveling of the roles of hnRNPs is conducive to establishing potential biomarkers and developing better intervention strategies by targeting these hnRNPs in the corresponding disorders. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

自身免疫性疾病的主要特征是由于对特定自身抗原的耐受性丧失而导致的自身反应性异常,尽管与免疫反应稳态相关的多种途径参与了疾病的启动或加重。异质核核糖核蛋白(hnRNPs)是一类广泛存在于多种细胞中的rna结合蛋白,因其在神经退行性疾病和癌症等疾病的核酸代谢和发病机制中具有独特的作用而备受关注。然而,hnRNPs与自身免疫性疾病之间的相互作用尚未完全阐明。事实上,hnRNPs的各种家族成员越来越多地被确定为免疫参与者,并与各种免疫相关的过程有关,包括免疫系统发育和先天或适应性免疫反应。具体来说,hnRNPs已被广泛认为是自身抗原,甚至超越了无数自身免疫性疾病,但它们的诊断和预后价值似乎被低估了。分子模仿、表位扩散和旁观者激活可能是hnRNPs自身抗体存在的主要推测机制。此外,hnRNPs通过与其他组分(特别是microRNAs和长链非编码rna)相互作用,在调节控制遗传易感性、疾病相关功能通路或免疫反应的关键基因表达方面发挥关键作用,从而促进炎症和自身免疫以及特定疾病表型。因此,全面揭示hnRNPs的作用有助于建立潜在的生物标志物,并通过针对这些hnRNPs在相应疾病中制定更好的干预策略。本文分类为:RNA在疾病和发展中的作用> RNA在疾病中的作用RNA与蛋白质和其他分子的相互作用>蛋白质-RNA相互作用:功能意义。
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引用次数: 0
Noncoding RNA mutations in cancer. 癌症中的非编码RNA突变。
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-08-06 DOI: 10.1002/wrna.1812
Honghong Zhou, Xinpei Hao, Peng Zhang, Shunmin He

Cancer is driven by both germline and somatic genetic changes. Efforts have been devoted to characterizing essential genetic variations in cancer initiation and development. Most attention has been given to mutations in protein-coding genes and associated regulatory elements such as promoters and enhancers. The development of sequencing technologies and in silico and experimental methods has allowed further exploration of cancer predisposition variants and important somatic mutations in noncoding RNAs, mainly for long noncoding RNAs and microRNAs. Association studies including GWAS have revealed hereditary variations including SNPs and indels in lncRNA or miRNA genes and regulatory regions. These mutations altered RNA secondary structures, expression levels, and target recognition and then conferred cancer predisposition to carriers. Whole-exome/genome sequencing comparing cancer and normal tissues has revealed important somatic mutations in noncoding RNA genes. Mutation hotspots and somatic copy number alterations have been identified in various tumor-associated noncoding RNAs. Increasing focus and effort have been devoted to studying the noncoding region of the genome. The complex genetic network of cancer initiation is being unveiled. This article is categorized under: RNA in Disease and Development > RNA in Disease.

癌症是由生殖细胞和体细胞基因变化驱动的。人们一直致力于描述癌症发生和发展过程中的基本遗传变异。大多数的注意力都集中在蛋白质编码基因的突变和相关的调控元件,如启动子和增强子。测序技术以及计算机和实验方法的发展,使得进一步探索非编码rna(主要是长链非编码rna和microrna)的癌症易感性变异和重要体细胞突变成为可能。包括GWAS在内的关联研究揭示了lncRNA或miRNA基因和调控区域的遗传变异,包括snp和indes。这些突变改变了RNA的二级结构、表达水平和靶标识别,然后赋予携带者癌症易感性。全外显子组/基因组测序比较了癌症和正常组织,揭示了非编码RNA基因的重要体细胞突变。在各种肿瘤相关的非编码rna中已经发现了突变热点和体细胞拷贝数改变。对基因组非编码区域的研究越来越受到人们的关注和重视。癌症起源的复杂基因网络正在被揭开。本文分类如下:RNA在疾病和发展> RNA在疾病。
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引用次数: 1
SKI complex: A multifaceted cytoplasmic RNA exosome cofactor in mRNA metabolism with links to disease, developmental processes, and antiviral responses. SKI复合物:与疾病、发育过程和抗病毒反应相关的mRNA代谢的细胞质RNA外泌体辅助因子。
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-06-29 DOI: 10.1002/wrna.1795
Rafal Tomecki, Karolina Drazkowska, Kamil Kobylecki, Agnieszka Tudek

RNA stability and quality control are integral parts of gene expression regulation. A key factor shaping eukaryotic transcriptomes, mainly via 3'-5' exoribonucleolytic trimming or degradation of diverse transcripts in nuclear and cytoplasmic compartments, is the RNA exosome. Precise exosome targeting to various RNA molecules requires strict collaboration with specialized auxiliary factors, which facilitate interactions with its substrates. The predominant class of cytoplasmic RNA targeted by the exosome are protein-coding transcripts, which are carefully scrutinized for errors during translation. Normal, functional mRNAs are turned over following protein synthesis by the exosome or by Xrn1 5'-3'-exonuclease, acting in concert with Dcp1/2 decapping complex. In turn, aberrant transcripts are eliminated by dedicated surveillance pathways, triggered whenever ribosome translocation is impaired. Cytoplasmic 3'-5' mRNA decay and surveillance are dependent on the tight cooperation between the exosome and its evolutionary conserved co-factor-the SKI (superkiller) complex (SKIc). Here, we summarize recent findings from structural, biochemical, and functional studies of SKIc roles in controlling cytoplasmic RNA metabolism, including links to various cellular processes. Mechanism of SKIc action is illuminated by presentation of its spatial structure and details of its interactions with exosome and ribosome. Furthermore, contribution of SKIc and exosome to various mRNA decay pathways, usually converging on recycling of ribosomal subunits, is delineated. A crucial physiological role of SKIc is emphasized by describing association between its dysfunction and devastating human disease-a trichohepatoenteric syndrome (THES). Eventually, we discuss SKIc functions in the regulation of antiviral defense systems, cell signaling and developmental transitions, emerging from interdisciplinary investigations. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.

RNA的稳定性和质量控制是基因表达调控的重要组成部分。形成真核生物转录组的一个关键因素是RNA外泌体,主要是通过细胞核和细胞质室中不同转录物的3'-5'外核糖核溶解修剪或降解。精确靶向各种RNA分子的外泌体需要与专门的辅助因子严格合作,这些辅助因子促进其与底物的相互作用。外泌体靶向的细胞质RNA的主要类别是蛋白质编码转录物,在翻译过程中仔细检查其错误。正常的功能性mrna在外泌体或Xrn1 5'-3'-外切酶与Dcp1/2脱冠复合物协同作用合成蛋白质后被翻转。反过来,异常转录本被专用的监视途径消除,核糖体易位受损时触发。胞质3'-5' mRNA的衰变和监视依赖于外泌体及其进化保守的辅助因子SKI(超级杀手)复合物(SKIc)之间的紧密合作。在这里,我们总结了最近关于SKIc在控制细胞质RNA代谢中的作用的结构、生化和功能研究的发现,包括与各种细胞过程的联系。SKIc的作用机制通过介绍其空间结构和与外泌体和核糖体相互作用的细节来阐明。此外,SKIc和外泌体对各种mRNA衰变途径的贡献,通常集中在核糖体亚基的再循环上。通过描述SKIc功能障碍与破坏性人类疾病(trichoho肝肠综合征)之间的关联,强调了SKIc的重要生理作用。最后,我们讨论了跨学科研究中出现的SKIc在抗病毒防御系统、细胞信号传导和发育转变调控中的功能。本文分为:RNA周转和监视>周转/监视机制RNA周转和监视> RNA稳定性调控RNA与蛋白质和其他分子的相互作用> RNA-蛋白质复合物。
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引用次数: 1
Hitting the mark: Localization of mRNA and biomolecular condensates in health and disease. 击中目标:mRNA和生物分子凝聚物在健康和疾病中的定位。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-07-02 DOI: 10.1002/wrna.1807
Jessica P Otis, Kimberly L Mowry

Subcellular mRNA localization is critical to a multitude of biological processes such as development of cellular polarity, embryogenesis, tissue differentiation, protein complex formation, cell migration, and rapid responses to environmental stimuli and synaptic depolarization. Our understanding of the mechanisms of mRNA localization must now be revised to include formation and trafficking of biomolecular condensates, as several biomolecular condensates that transport and localize mRNA have recently been discovered. Disruptions in mRNA localization can have catastrophic effects on developmental processes and biomolecular condensate biology and have been shown to contribute to diverse diseases. A fundamental understanding of mRNA localization is essential to understanding how aberrations in this biology contribute the etiology of numerous cancers though support of cancer cell migration and biomolecular condensate dysregulation, as well as many neurodegenerative diseases, through misregulation of mRNA localization and biomolecular condensate biology. This article is categorized under: RNA Export and Localization > RNA Localization RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

亚细胞mRNA定位对许多生物过程至关重要,如细胞极性发育、胚胎发生、组织分化、蛋白质复合物形成、细胞迁移、对环境刺激和突触去极化的快速反应。我们对mRNA定位机制的理解现在必须修正,以包括生物分子凝聚体的形成和运输,因为最近发现了几种运输和定位mRNA的生物分子凝聚体。mRNA定位的中断可能对发育过程和生物分子凝聚生物学产生灾难性影响,并已被证明与多种疾病有关。对mRNA定位的基本理解对于理解这种生物学异常如何通过支持癌细胞迁移和生物分子凝聚失调来促进许多癌症的病因至关重要,以及通过mRNA定位和生物分子凝聚生物学的失调来促进许多神经退行性疾病。本文分类为:RNA输出和定位> RNA定位RNA在疾病和发展> RNA在疾病RNA在疾病和发展> RNA在发展。
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引用次数: 0
Proteostasis regulation through ribosome quality control and no-go-decay. 通过核糖体质量控制和无衰变来调节蛋白质稳态。
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-07-24 DOI: 10.1002/wrna.1809
Lokha Ranjani Alagar Boopathy, Emma Beadle, Aitana Garcia-Bueno Rico, Maria Vera

Cell functionality relies on the existing pool of proteins and their folding into functional conformations. This is achieved through the regulation of protein synthesis, which requires error-free mRNAs and ribosomes. Ribosomes are quality control hubs for mRNAs and proteins. Problems during translation elongation slow down the decoding rate, leading to ribosome halting and the eventual collision with the next ribosome. Collided ribosomes form a specific disome structure recognized and solved by ribosome quality control (RQC) mechanisms. RQC pathways orchestrate the degradation of the problematic mRNA by no-go decay and the truncated nascent peptide, the repression of translation initiation, and the recycling of the stalled ribosomes. All these events maintain protein homeostasis and return valuable ribosomes to translation. As such, cell homeostasis and function are maintained at the mRNA level by preventing the production of aberrant or unnecessary proteins. It is becoming evident that the crosstalk between RQC and the protein homeostasis network is vital for cell function, as the absence of RQC components leads to the activation of stress response and neurodegenerative diseases. Here, we review the molecular events of RQC discovered through well-designed stalling reporters. Given the impact of RQC in proteostasis, we discuss the relevance of identifying endogenous mRNA regulated by RQC and their preservation in stress conditions. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms Translation > Regulation.

细胞的功能依赖于现有的蛋白质池及其折叠成功能性构象。这是通过调节蛋白质合成来实现的,这需要无错误的mrna和核糖体。核糖体是mrna和蛋白质的质量控制中心。翻译延伸过程中的问题减慢了解码速率,导致核糖体停止并最终与下一个核糖体碰撞。碰撞核糖体形成特定的二体结构,由核糖体质量控制(RQC)机制识别和解决。RQC通路通过no-go衰变和截断新生肽,翻译起始的抑制和停滞核糖体的再循环来协调问题mRNA的降解。所有这些事件都维持了蛋白质的稳态,并使有价值的核糖体恢复翻译。因此,通过防止产生异常或不必要的蛋白质,细胞的稳态和功能维持在mRNA水平。越来越明显的是,RQC和蛋白质稳态网络之间的串扰对细胞功能至关重要,因为RQC成分的缺失会导致应激反应的激活和神经退行性疾病。在这里,我们回顾了通过精心设计的失速记者发现的RQC分子事件。鉴于RQC在蛋白质静止中的影响,我们讨论了鉴定由RQC调节的内源性mRNA及其在应激条件下的保存的相关性。本文分类如下:RNA周转和监视>周转/监视机制翻译>调控。
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引用次数: 0
Correction to "A little less aggregation a little more replication: Viral manipulation of stress granules". 更正“少一点聚集多一点复制:压力颗粒的病毒操纵”。
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-10-03 DOI: 10.1002/wrna.1821
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引用次数: 0
The tip of the iceberg-The roles of long noncoding RNAs in acute myeloid leukemia. 冰山一角——长链非编码rna在急性髓性白血病中的作用。
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-06-02 DOI: 10.1002/wrna.1796
Patrick Connerty, Richard B Lock

Long noncoding RNAs (lncRNAs) are traditionally defined as RNA transcripts longer than 200 nucleotides that have no protein coding potential. LncRNAs have been identified to be dysregulated in various types of cancer, including the deadly hematopoietic cancer-acute myeloid leukemia (AML). Currently, survival rates for AML have reached a plateau necessitating new therapeutic targets and biomarkers to improve treatment options and survival from the disease. Therefore, the identification of lncRNAs as novel biomarkers and therapeutic targets for AML has major benefits. In this review, we assess the key studies which have recently identified lncRNAs as important molecules in AML and summarize the current knowledge of lncRNAs in AML. We delve into examples of the specific roles of lncRNA action in AML such as driving proliferation, differentiation block and therapy resistance as well as their function as tumor suppressors and utility as biomarkers. This article is categorized under: RNA in Disease and Development > RNA in Disease.

长链非编码RNA (lncrna)传统上被定义为长度超过200个核苷酸的RNA转录物,没有蛋白质编码潜力。lncrna已被发现在各种类型的癌症中失调,包括致命的造血癌症——急性髓性白血病(AML)。目前,AML的生存率已经达到平台期,需要新的治疗靶点和生物标志物来改善治疗选择和疾病的生存率。因此,鉴定lncrna作为AML的新型生物标志物和治疗靶点具有重大的益处。在这篇综述中,我们评估了最近发现lncRNAs在AML中是重要分子的关键研究,并总结了目前对AML中lncRNAs的认识。我们深入研究了lncRNA在AML中具体作用的例子,如驱动增殖、分化阻断和治疗耐药性,以及它们作为肿瘤抑制因子的功能和作为生物标志物的效用。本文分类如下:RNA在疾病和发展> RNA在疾病。
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引用次数: 0
Progress of CRISPR-based programmable RNA manipulation and detection. 基于crispr的可编程RNA操作与检测研究进展。
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-06-06 DOI: 10.1002/wrna.1804
Beibei Wang, Hui Yang

Prokaryotic clustered regularly interspaced short palindromic repeats and CRISPR associated (CRISPR-Cas) systems provide adaptive immunity by using RNA-guided endonucleases to recognize and eliminate invading foreign nucleic acids. Type II Cas9, type V Cas12, type VI Cas13, and type III Csm/Cmr complexes have been well characterized and developed as programmable platforms for selectively targeting and manipulating RNA molecules of interest in prokaryotic and eukaryotic cells. These Cas effectors exhibit remarkable diversity of ribonucleoprotein (RNP) composition, target recognition and cleavage mechanisms, and self discrimination mechanisms, which are leveraged for various RNA targeting applications. Here, we summarize the current understanding of mechanistic and functional characteristics of these Cas effectors, give an overview on RNA detection and manipulation toolbox established so far including knockdown, editing, imaging, modification, and mapping RNA-protein interactions, and discuss the future directions for CRISPR-based RNA targeting tools. This article is categorized under: RNA Methods > RNA Analyses in Cells RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

原核生物集群定期间隔的短回文重复序列和CRISPR相关(CRISPR- cas)系统通过rna引导的内切酶识别和消除入侵的外来核酸提供适应性免疫。II型Cas9、V型Cas12、VI型Cas13和III型Csm/Cmr复合物已被很好地表征并开发为可编程平台,用于选择性靶向和操纵原核和真核细胞中感兴趣的RNA分子。这些Cas效应物表现出显著的核糖核蛋白(RNP)组成、靶标识别和切割机制以及自我区分机制的多样性,可用于各种RNA靶向应用。在这里,我们总结了目前对这些Cas效应物的机制和功能特征的理解,概述了迄今为止建立的RNA检测和操作工具箱,包括敲除、编辑、成像、修饰和绘制RNA-蛋白相互作用,并讨论了基于crispr的RNA靶向工具的未来发展方向。本文分类如下:RNA方法>细胞中的RNA分析RNA加工> RNA编辑和修饰RNA与蛋白质和其他分子的相互作用>蛋白质-RNA相互作用:功能意义。
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引用次数: 0
期刊
Wiley Interdisciplinary Reviews: RNA
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