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Transcription Kinetics in the Coronavirus Life Cycle. 冠状病毒生命周期中的转录动力学。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-01-01 DOI: 10.1002/wrna.70000
Katarzyna Grelewska-Nowotko, Ahmed Eisa Elhag, Tomasz Wojciech Turowski

Coronaviruses utilize a positive-sense single-strand RNA, functioning simultaneously as mRNA and the genome. An RNA-dependent RNA polymerase (RdRP) plays a dual role in transcribing genes and replicating the genome, making RdRP a critical target in therapies against coronaviruses. This review explores recent advancements in understanding the coronavirus transcription machinery, discusses it within virus infection context, and incorporates kinetic considerations on RdRP activity. We also address steric limitations in coronavirus replication, particularly during early infection phases, and outline hypothesis regarding translation-transcription conflicts, postulating the existence of mechanisms that resolve these issues. In cells infected by coronaviruses, abundant structural proteins are synthesized from subgenomic RNA fragments (sgRNAs) produced via discontinuous transcription. During elongation, RdRP can skip large sections of the viral genome, resulting in the creation of shorter sgRNAs that reflects the stoichiometry of viral structural proteins. Although the precise mechanism of discontinuous transcription remains unknown, we discuss recent hypotheses involving long-distance RNA-RNA interactions, helicase-mediated RdRP backtracking, dissociation and reassociation of RdRP, and RdRP dimerization.

冠状病毒利用正义单链RNA,同时作为mRNA和基因组发挥作用。RNA依赖性RNA聚合酶(RdRP)在转录基因和复制基因组中发挥双重作用,使RdRP成为治疗冠状病毒的关键靶点。这篇综述探讨了了解冠状病毒转录机制的最新进展,在病毒感染背景下讨论了它,并纳入了对RdRP活性的动力学考虑。我们还讨论了冠状病毒复制的空间限制,特别是在早期感染阶段,并概述了关于翻译-转录冲突的假设,假设存在解决这些问题的机制。在被冠状病毒感染的细胞中,亚基因组RNA片段(sgRNAs)通过不连续转录产生,合成了大量的结构蛋白。在延伸过程中,RdRP可以跳过病毒基因组的大部分,从而产生更短的sgrna,这反映了病毒结构蛋白的化学计量。尽管不连续转录的确切机制尚不清楚,但我们讨论了最近的假设,包括长距离RNA-RNA相互作用,解旋酶介导的RdRP回溯,RdRP的解离和重新结合以及RdRP二聚化。
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引用次数: 0
Hypothesis for Molecular Evolution in the Pre-Cellular Stage of the Origin of Life. 生命起源前细胞阶段的分子进化假说。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-01-01 DOI: 10.1002/wrna.70001
Yong Wang, Yiling Du

Life was originated from inorganic world and had experienced a long period of evolution in about 3.8 billion years. The time for emergence of the pioneer creations on Earth is debatable nowadays, and how the scenario for the prebiotic molecular interactions is still mysterious. Before the spreading of cellular organisms, chemical evolution was perhaps prevailing for millions of years, in which inorganic biosynthesis was ultimately replaced by biochemical reactions. Understanding the major molecular players and their interactions toward cellular life is fundamental for current medical science and extraterrestrial life exploration. In this review, we propose a road map for the primordial molecular evolution in early Earth, which probably occurred adjacent to hydrothermal vents with a strong gradient of organic molecules, temperature, and metal contents. Natural selection of the macromolecules with strong secondary structures and catalytic centers is associated with decreasing of overall entropy of the biopolymers. Our review may shed lights into the important selection of gene-coding RNA with secondary structures from large amounts of random biopolymers and formation of ancient ribosomes with biological machines supporting the basic life processes. Integration of the free environmental ribosomes by the early cellular life as symbiotic molecular machines is probably the earliest symbiosis on Earth.

生命起源于无机世界,经历了约38亿年的漫长演化过程。如今,地球上最早的生物出现的时间是有争议的,而益生元分子相互作用的情况仍然是个谜。在细胞生物扩散之前,化学进化可能盛行了数百万年,其中无机生物合成最终被生化反应所取代。了解主要的分子参与者及其与细胞生命的相互作用是当前医学和地外生命探索的基础。在这篇综述中,我们提出了地球早期原始分子演化的路线图,它可能发生在有机分子、温度和金属含量梯度很强的热液喷口附近。具有强二级结构和催化中心的大分子的自然选择与生物聚合物总熵的降低有关。我们的研究可能有助于揭示从大量随机生物聚合物中选择具有二级结构的基因编码RNA的重要过程,以及支持基本生命过程的生物机器形成古老核糖体的过程。早期细胞生命将自由的环境核糖体整合为共生分子机器,这可能是地球上最早的共生现象。
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引用次数: 0
Contribution of DNA/RNA Structures Formed by Expanded CGG/CCG Repeats Within the FMR1 Locus in the Pathogenesis of Fragile X-Associated Disorders. FMR1基因座内扩展的CGG/CCG重复序列形成的DNA/RNA结构对脆性X相关疾病发病机制的贡献
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1002/wrna.1874
Izabela Broniarek, Daria Niewiadomska, Krzysztof Sobczak

Repeat expansion disorders (REDs) encompass over 50 inherited neurological disorders and are characterized by the expansion of short tandem nucleotide repeats beyond a specific repeat length. Particularly intriguing among these are multiple fragile X-associated disorders (FXds), which arise from an expansion of CGG repeats in the 5' untranslated region of the FMR1 gene. Despite arising from repeat expansions in the same gene, the clinical manifestations of FXds vary widely, encompassing developmental delays, parkinsonism, dementia, and an increased risk of infertility. FXds also exhibit molecular mechanisms observed in other REDs, that is, gene- and protein-loss-of-function and RNA- and protein-gain-of-function. The heterogeneity of phenotypes and pathomechanisms in FXds results from the different lengths of the CGG tract. As the number of repeats increases, the structures formed by RNA and DNA fragments containing CGG repeats change significantly, contributing to the diversity of FXd phenotypes and mechanisms. In this review, we discuss the role of RNA and DNA structures formed by expanded CGG repeats in driving FXd pathogenesis and how the genetic instability of CGG repeats is mediated by the complex interplay between transcription, DNA replication, and repair. We also discuss therapeutic strategies, including small molecules, antisense oligonucleotides, and CRISPR-Cas systems, that target toxic RNA and DNA involved in the development of FXds.

重复扩增性疾病(REDs)包括 50 多种遗传性神经系统疾病,其特征是短串联核苷酸重复序列的扩增超过了特定的重复长度。其中尤为引人关注的是多发性脆性 X 相关疾病(FXds),它是由 FMR1 基因 5' 非翻译区的 CGG 重复序列扩增引起的。尽管脆性 X 相关疾病是由同一基因的重复扩增引起的,但其临床表现却千差万别,包括发育迟缓、帕金森氏症、痴呆症和不孕不育风险增加。FXds 还表现出在其他 REDs 中观察到的分子机制,即基因和蛋白功能缺失以及 RNA 和蛋白功能增益。FXds 表型和病理机制的异质性源于 CGG 道的不同长度。随着重复序列数量的增加,含有 CGG 重复序列的 RNA 和 DNA 片段所形成的结构也会发生显著变化,从而导致 FXd 表型和机制的多样性。在这篇综述中,我们将讨论由扩展的 CGG 重复序列形成的 RNA 和 DNA 结构在驱动 FXd 发病机制中的作用,以及 CGG 重复序列的遗传不稳定性是如何通过转录、DNA 复制和修复之间复杂的相互作用来介导的。我们还讨论了针对参与 FXds 发病的有毒 RNA 和 DNA 的治疗策略,包括小分子、反义寡核苷酸和 CRISPR-Cas 系统。
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引用次数: 0
The Unusual Role of Ribonuclease L in Innate Immunity. 核糖核酸酶L在先天免疫中的特殊作用。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1002/wrna.1878
Agnes Karasik, Nicholas R Guydosh

Ribonuclease L is an endonuclease that is activated as part of the dsRNA-driven innate immune response. Active RNase L cleaves pathogenic RNAs as a way to eliminate infections. However, there are additional and unexpected ways that RNase L causes changes in the host that promote an immune response and contribute to its role in host defense. Central to these unconventional mechanisms is the observation that RNase L also degrades the mRNA of the host. In turn, mRNA fragments that RNase L generates can be translated. This causes activation of a ribosome collision sensor that leads to downstream signaling and cell death. Additionally, the liberation of RNA binding proteins after RNA decay appears to affect gene expression. In this review, we discuss these and other recent advances that focus on novel and unusual ways RNase L contributes to innate immunity.

核糖核酸酶L是一种内切酶,作为dsrna驱动的先天免疫反应的一部分被激活。活性rna酶L切割致病rna作为消除感染的一种方式。然而,RNase L还可以通过其他意想不到的方式引起宿主的变化,从而促进免疫反应并促进其在宿主防御中的作用。这些非常规机制的核心是观察到RNase L也会降解宿主的mRNA。反过来,RNase L产生的mRNA片段可以被翻译。这导致核糖体碰撞传感器的激活,导致下游信号传导和细胞死亡。此外,RNA衰变后RNA结合蛋白的释放似乎会影响基因表达。在这篇综述中,我们讨论了这些和其他最近的进展,重点是RNase L促进先天免疫的新颖和不寻常的方式。
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引用次数: 0
Challenges in Therapeutically Targeting the RNA-Recognition Motif. 靶向rna识别基序治疗的挑战。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1002/wrna.1877
Stefan Schmeing, Peter 't Hart

The RNA recognition motif (RRM) is the most common RNA binding domain found in the human proteome. RRM domains provide RNA-binding proteins with sequence specific RNA recognition allowing them to participate in RNA-centric processes such as mRNA maturation, translation initiation, splicing, and RNA degradation. They are drivers of various diseases through overexpression or mutation, making them attractive therapeutic targets and addressing these proteins through their RRM domains with chemical compounds is gaining ever more attention. However, it is still very challenging to find selective and potent RNA-competitors due to the small size of the domain and high structural conservation of its RNA binding interface. Despite these challenges, a selection of compounds has been reported for several RRM containing proteins, but often with limited biophysical evidence and low selectivity. A solution to selectively targeting RRM domains might be through avoiding the RNA-binding surface altogether, but rather look for composite pockets formed with other proteins or for protein-protein interaction sites that regulate the target's activity but are less conserved. Alternative modalities, such as oligonucleotides, peptides, and molecular glues, are exciting new approaches to address these challenging targets and achieve the goal of therapeutic intervention at the RNA regulatory level.

RNA识别基序(RRM)是人类蛋白质组中最常见的RNA结合结构域。RRM结构域为RNA结合蛋白提供序列特异性RNA识别,使它们能够参与RNA中心过程,如mRNA成熟、翻译起始、剪接和RNA降解。它们通过过度表达或突变是各种疾病的驱动因素,使它们成为有吸引力的治疗靶点,并且通过它们的RRM结构域与化合物解决这些蛋白质正获得越来越多的关注。然而,由于结构域的小尺寸和其RNA结合界面的高度结构保守性,寻找选择性和有效的RNA竞争对手仍然是非常具有挑战性的。尽管存在这些挑战,已经报道了几种含有蛋白质的RRM的化合物选择,但通常生物物理证据有限,选择性低。选择性靶向RRM结构域的解决方案可能是完全避免rna结合表面,而是寻找与其他蛋白质形成的复合口袋或蛋白质-蛋白质相互作用位点,这些位点调节靶标的活性,但不太保守。替代方法,如寡核苷酸、多肽和分子胶,是令人兴奋的新方法,可以解决这些具有挑战性的目标,并在RNA调控水平上实现治疗干预的目标。
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引用次数: 0
Integrated Biochemical and Computational Methods for Deciphering RNA-Processing Codes. 破译 RNA 处理密码的生化和计算综合方法。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1002/wrna.1875
Chen Du, Weiliang Fan, Yu Zhou

RNA processing involves steps such as capping, splicing, polyadenylation, modification, and nuclear export. These steps are essential for transforming genetic information in DNA into proteins and contribute to RNA diversity and complexity. Many biochemical methods have been developed to profile and quantify RNAs, as well as to identify the interactions between RNAs and RNA-binding proteins (RBPs), especially when coupled with high-throughput sequencing technologies. With the rapid accumulation of diverse data, it is crucial to develop computational methods to convert the big data into biological knowledge. In particular, machine learning and deep learning models are commonly utilized to learn the rules or codes governing the transformation from DNA sequences to intriguing RNAs based on manually designed or automatically extracted features. When precise enough, the RNA codes can be incredibly useful for predicting RNA products, decoding the molecular mechanisms, forecasting the impact of disease variants on RNA processing events, and identifying driver mutations. In this review, we systematically summarize the biochemical and computational methods for deciphering five important RNA codes related to alternative splicing, alternative polyadenylation, RNA localization, RNA modifications, and RBP binding. For each code, we review the main types of experimental methods used to generate training data, as well as the key features, strategic model structures, and advantages of representative tools. We also discuss the challenges encountered in developing predictive models using large language models and extensive domain knowledge. Additionally, we highlight useful resources and propose ways to improve computational tools for studying RNA codes.

RNA 加工包括加帽、剪接、多聚腺苷酸化、修饰和核输出等步骤。这些步骤对于将 DNA 中的遗传信息转化为蛋白质至关重要,也是造成 RNA 多样性和复杂性的原因。目前已开发出许多生化方法来剖析和量化 RNA,以及识别 RNA 与 RNA 结合蛋白(RBPs)之间的相互作用,尤其是与高通量测序技术相结合时。随着各种数据的快速积累,开发将大数据转化为生物学知识的计算方法至关重要。特别是,机器学习和深度学习模型通常被用来根据人工设计或自动提取的特征,学习管理从 DNA 序列到引人入胜的 RNA 的转化的规则或代码。如果足够精确,RNA 代码在预测 RNA 产物、解码分子机制、预测疾病变异对 RNA 处理事件的影响以及识别驱动突变等方面可以发挥难以置信的作用。在这篇综述中,我们系统地总结了破译与替代剪接、替代多腺苷酸化、RNA 定位、RNA 修饰和 RBP 结合有关的五种重要 RNA 代码的生化和计算方法。针对每种代码,我们回顾了用于生成训练数据的主要实验方法类型,以及代表性工具的关键特征、战略模型结构和优势。我们还讨论了使用大型语言模型和广泛的领域知识开发预测模型时遇到的挑战。此外,我们还强调了有用的资源,并提出了改进研究 RNA 代码的计算工具的方法。
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引用次数: 0
Three Stages of Nascent Protein Translocation Through the Ribosome Exit Tunnel. 新生蛋白质通过核糖体出口隧道转运的三个阶段
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1002/wrna.1873
Michal H Kolář, Hugo McGrath, Felipe C Nepomuceno, Michaela Černeková

All proteins in living organisms are produced in ribosomes that facilitate the translation of genetic information into a sequence of amino acid residues. During translation, the ribosome undergoes initiation, elongation, termination, and recycling. In fact, peptide bonds are formed only during the elongation phase, which comprises periodic association of transfer RNAs and multiple auxiliary proteins with the ribosome and the addition of an amino acid to the nascent polypeptide one at a time. The protein spends a considerable amount of time attached to the ribosome. Here, we conceptually divide this portion of the protein lifetime into three stages. We define each stage on the basis of the position of the N-terminus of the nascent polypeptide within the ribosome exit tunnel and the context of the catalytic center. We argue that nascent polypeptides experience a variety of forces that determine how they translocate through the tunnel and interact with the tunnel walls. We review current knowledge about nascent polypeptide translocation and identify several white spots in our understanding of the birth of proteins.

生物体内的所有蛋白质都是在核糖体中产生的,核糖体可将遗传信息翻译成氨基酸残基序列。在翻译过程中,核糖体经历了启动、延伸、终止和再循环。事实上,只有在延伸阶段才会形成肽键,该阶段包括转移核糖核酸和多种辅助蛋白质与核糖体的周期性结合,以及在新生多肽中一次添加一个氨基酸。蛋白质在核糖体上附着的时间相当长。在这里,我们从概念上将这部分蛋白质的生命周期分为三个阶段。我们根据新生多肽 N 端在核糖体出口隧道中的位置和催化中心的环境来定义每个阶段。我们认为,新生多肽会经历各种作用力,这些作用力决定了它们如何通过隧道并与隧道壁相互作用。我们回顾了目前有关新生多肽转运的知识,并指出了我们对蛋白质诞生的理解中的几个白点。
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引用次数: 0
Current Understandings and Open Hypotheses on Extracellular Circular RNAs. 关于细胞外环状 RNA 的现有认识和开放性假设。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1002/wrna.1872
Jasper Verwilt, Marieke Vromman

Circular RNAs (circRNAs) are closed RNA loops present in humans and other organisms. Various circRNAs have an essential role in diseases, including cancer. Cells can release circRNAs into the extracellular space of adjacent biofluids and can be present in extracellular vesicles. Due to their circular nature, extracellular circRNAs (excircRNAs) are more stable than their linear counterparts and are abundant in many biofluids, such as blood plasma and urine. circRNAs' link with disease suggests their extracellular counterparts have high biomarker potential. However, circRNAs and the extracellular space are challenging research domains, as they consist of complex biological systems plagued with nomenclature issues and a wide variety of protocols with different advantages and disadvantages. Here, we summarize what is known about excircRNAs, the current challenges in the field, and what is needed to improve extracellular circRNA research.

环状 RNA(circRNA)是存在于人类和其他生物体内的闭合 RNA 环。各种 circRNA 在疾病(包括癌症)中发挥着重要作用。细胞可将 circRNA 释放到邻近生物流体的细胞外空间,也可存在于细胞外囊泡中。由于细胞外 circRNAs(excircRNAs)具有环状性质,因此比其线性对应物更稳定,在血浆和尿液等许多生物流体中含量丰富。circRNAs 与疾病的联系表明,其细胞外对应物具有很高的生物标记潜力。然而,circRNAs 和细胞外空间是极具挑战性的研究领域,因为它们由复杂的生物系统组成,存在着命名问题和优缺点各异的各种方案。在此,我们总结了人们对细胞外 circRNA 的了解、该领域目前面临的挑战以及改进细胞外 circRNA 研究的需要。
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引用次数: 0
Decoding the role of RNA sequences and their interactions in influenza A virus infection and adaptation. 解码 RNA 序列及其相互作用在甲型流感病毒感染和适应中的作用。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1002/wrna.1871
Satya P Sharma, Mamta Chawla-Sarkar, Rajat Sandhir, Dipanjan Dutta

Influenza viruses (types A, B, C, and D) belong to the family orthomyxoviridae. Out of all the influenza types, influenza A virus (IAV) causes human pandemic outbreaks. Its pandemic potential is predominantly attributed to the genetic reassortment favored by a broad spectrum of host species that could lead to an antigenic shift along with a high rate of mutations in its genome, presenting a possibility of subtypes with heightened pathogenesis and virulence in humans (antigenic drift). In addition to antigenic shift and drift, there are several other inherent properties of its viral RNA species (vRNA, vmRNA, and cRNA) that significantly contribute to the success of specific stages of viral infection. In this review, we compile the key features of IAV RNA, such as sequence motifs and secondary structures, their functional significance in the infection cycle, and their overall impact on the virus's adaptive and evolutionary fitness. Because many of these motifs and folds are conserved, we also assess the existing antiviral approaches focused on targeting IAV RNA. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.

流感病毒(甲型、乙型、丙型和丁型)属于正粘病毒科。在所有流感病毒类型中,甲型流感病毒(IAV)会导致人类流感大爆发。甲型流感病毒之所以具有大流行的潜能,主要是由于其基因重组受到广泛宿主物种的青睐,这可能导致抗原转变以及基因组的高突变率,从而可能产生对人类具有更强致病性和毒力的亚型(抗原漂移)。除抗原转移和漂移外,病毒 RNA(vRNA、vmRNA 和 cRNA)还具有其他一些固有特性,这些特性对病毒感染特定阶段的成功起着重要作用。在这篇综述中,我们梳理了 IAV RNA 的关键特征,如序列基序和二级结构、它们在感染周期中的功能意义,以及它们对病毒适应性和进化适应性的总体影响。由于这些基序和褶皱中有许多是保守的,因此我们还评估了现有的以 IAV RNA 为靶标的抗病毒方法。本文归类于RNA 结构与动力学 > RNA 结构对生物系统的影响 RNA 与蛋白质和其他分子的相互作用 > 蛋白质与 RNA 的相互作用:疾病和发育中的 RNA > 疾病中的 RNA。
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引用次数: 0
The Definition of RNA Age Related to RNA Sequence Changes. 与RNA序列变化相关的RNA年龄的定义。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1002/wrna.1876
Zhongneng Xu, Shuichi Asakawa

Ribonucleic acid (RNA) undergoes dynamic changes in its structure and function under various intracellular and extracellular conditions over time. However, there is a lack of research on the concept of the RNA age to describe its diverse fates. This study proposes a definition of RNA age to address this issue. RNA age was defined as a sequence of numbers wherein the elements in the sequence were the nucleotide ages of the ribonucleotide residues in the RNA. Mean nucleotide age was used to represent RNA age. This definition describes the temporal properties of RNAs that have undergone diverse life histories and reflects the dynamic state of each ribonucleotide residue, which can be expressed mathematically. Notably, events (including base insertions, base deletions, and base substitutions) are likely to cause RNA to become younger or older when using mean nucleotide ages to represent the RNA age. Although information, including the presence of added markers in RNA, chemical modification structure of the RNA, and the excision of introns in the mRNA in cells, may provide a basis for identifying RNA age, little is known about determining the RNA age of extracellular RNA in the wild. Nonetheless, we believe that RNA age has an important relationship with the diverse biological properties of RNA under intracellular and extracellular conditions. Therefore, our proposed definition of RNA age offers new perspectives for studying dynamic changes in RNA function, RNA aging, ancient RNA, environmental RNA, and the ages of other biomolecules.

随着时间的推移,核糖核酸(RNA)的结构和功能在不同的细胞内和细胞外条件下发生动态变化。然而,缺乏对RNA时代概念的研究来描述其多样化的命运。本研究提出了RNA年龄的定义来解决这个问题。RNA年龄被定义为一个数字序列,其中序列中的元素是RNA中核糖核苷酸残基的核苷酸年龄。平均核苷酸年龄表示RNA年龄。这个定义描述了经历了不同生活史的rna的时间性质,反映了每个核糖核苷酸残基的动态状态,可以用数学的方式表达。值得注意的是,当使用平均核苷酸年龄来表示RNA年龄时,事件(包括碱基插入、碱基缺失和碱基替换)可能会导致RNA变得更年轻或更老。虽然信息,包括RNA中添加标记物的存在、RNA的化学修饰结构以及细胞中mRNA内含子的切除,可能为鉴定RNA年龄提供了基础,但对于确定野生细胞外RNA的RNA年龄知之甚少。尽管如此,我们认为RNA年龄与RNA在细胞内和细胞外条件下的多种生物学特性有着重要的关系。因此,我们提出的RNA年龄定义为研究RNA功能、RNA老化、古代RNA、环境RNA和其他生物分子年龄的动态变化提供了新的视角。
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引用次数: 0
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Wiley Interdisciplinary Reviews: RNA
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