Annual review of biochemistry最新文献

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A Cool Look at Positive-Strand RNA Virus Replication Organelles: New Insights from Cryo–Electron Microscopy 正链 RNA 病毒复制细胞器的酷炫外观：冷冻电子显微镜的新发现

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2024-04-10 DOI: 10.1146/annurev-biochem-052521-115736

Nina L. de Beijer, Eric J. Snijder, Montserrat Bárcena

Positive-strand RNA viruses encompass a variety of established and emerging eukaryotic pathogens. Their genome replication is confined to specialized cytoplasmic membrane compartments known as replication organelles (ROs). These ROs derive from host membranes, transformed into distinct structures such as invaginated spherules or intricate membrane networks including single- and/or double-membrane vesicles. ROs play a vital role in orchestrating viral RNA synthesis and evading detection by innate immune sensors of the host. In recent years, groundbreaking cryo–electron microscopy studies conducted with several prototypic viruses have significantly advanced our understanding of RO structure and function. Notably, these studies unveiled the presence of crown-shaped multimeric viral protein complexes that seem to actively participate in viral RNA synthesis and regulate the release of newly synthesized RNA into the cytosol for translation and packaging. These findings have shed light on novel viral functions and fascinating macromolecular complexes that delineate promising new avenues for future research.

正链 RNA 病毒包括各种已确定的和新出现的真核病原体。它们的基因组复制仅限于被称为复制细胞器（ROs）的特化细胞质膜区。这些细胞器来源于宿主膜，并转化为独特的结构，如内陷球体或复杂的膜网络（包括单膜和/或双膜囊泡）。ROs 在协调病毒 RNA 合成和躲避宿主先天性免疫传感器检测方面发挥着重要作用。近年来，对几种原型病毒进行的突破性冷冻电镜研究极大地推动了我们对 RO 结构和功能的了解。值得注意的是，这些研究揭示了冠状多聚体病毒蛋白复合物的存在，它们似乎积极参与病毒 RNA 的合成，并调节新合成的 RNA 释放到细胞质中进行翻译和包装。这些发现揭示了新的病毒功能和引人入胜的大分子复合物，为今后的研究开辟了前景广阔的新途径。

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引用次数: 0

Replication and Transcription of Human Mitochondrial DNA 人类线粒体 DNA 的复制和转录

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2024-04-10 DOI: 10.1146/annurev-biochem-052621-092014

Maria Falkenberg, Nils-Göran Larsson, Claes M. Gustafsson

Mammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like DNA and RNA polymerases, and our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated by biochemistry and structural biology and essential in vivo roles established by cell biology and mouse genetics. Single molecules of mtDNA are packaged by mitochondrial transcription factor A into mitochondrial nucleoids, and their level of compaction influences the initiation of both replication and transcription. Mutations affecting the molecular machineries replicating and transcribing mtDNA are important causes of human mitochondrial disease, reflecting the critical role of the genome in oxidative phosphorylation system biogenesis. Mechanisms controlling mtDNA replication and transcription still need to be clarified, and future research in this area is likely to open novel therapeutic possibilities for treating mitochondrial dysfunction.

哺乳动物线粒体 DNA（mtDNA）通过噬菌体 DNA 和 RNA 聚合酶进行复制和转录，在过去的几十年中，我们对这些过程的了解取得了长足的进步。生物化学和结构生物学已经阐明了这些过程的分子机制，细胞生物学和小鼠遗传学也确定了这些过程在体内的重要作用。线粒体转录因子 A 将单分子 mtDNA 包装成线粒体核仁，其压实程度影响复制和转录的启动。影响复制和转录 mtDNA 分子机制的突变是导致人类线粒体疾病的重要原因，这反映了基因组在氧化磷酸化系统生物生成中的关键作用。控制 mtDNA 复制和转录的机制仍有待澄清，而这一领域的未来研究很可能为治疗线粒体功能障碍带来新的治疗可能性。

引用次数: 0

Replication–Transcription Conflicts: A Perpetual War on the Chromosome 复制-转录冲突：染色体上的持久战

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2024-04-10 DOI: 10.1146/annurev-biochem-030222-115809

Kaitlyn R. Browning, Houra Merrikh

DNA replication and transcription occur in all living cells across all domains of life. Both essential processes occur simultaneously on the same template, leading to conflicts between the macromolecular machines that perform these functions. Numerous studies over the past few decades demonstrate that this is an inevitable problem in both prokaryotic and eukaryotic cells. We have learned that conflicts lead to replication fork reversal, breaks in the DNA, R-loop formation, topological stress, and mutagenesis, and they can ultimately impact evolution. Recent studies have also provided insight into the various mechanisms that mitigate, resolve, and allow tolerance of conflicts and how conflicts result in divergent pathological consequences across divergent species. In this review, we summarize current knowledge regarding the outcomes of encounters between replication and transcription machineries and explore how these clashes are dealt with across species.

DNA 复制和转录发生在所有生命领域的所有活细胞中。这两个基本过程同时发生在同一个模板上，导致执行这些功能的大分子机器之间发生冲突。过去几十年的大量研究表明，这是原核细胞和真核细胞中不可避免的问题。我们了解到，冲突会导致复制叉逆转、DNA断裂、R环形成、拓扑压力和突变，并最终影响进化。最近的研究还让我们深入了解了缓解、解决和容忍冲突的各种机制，以及冲突如何导致不同物种产生不同的病理后果。在这篇综述中，我们总结了目前有关复制和转录机制之间冲突结果的知识，并探讨了不同物种如何处理这些冲突。

引用次数: 0

The Art and Science of Molecular Docking 分子对接的艺术与科学

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2024-04-10 DOI: 10.1146/annurev-biochem-030222-120000

Joseph M. Paggi, Ayush Pandit, Ron O. Dror

Molecular docking has become an essential part of a structural biologist's and medicinal chemist's toolkits. Given a chemical compound and the three-dimensional structure of a molecular target—for example, a protein—docking methods fit the compound into the target, predicting the compound's bound structure and binding energy. Docking can be used to discover novel ligands for a target by screening large virtual compound libraries. Docking can also provide a useful starting point for structure-based ligand optimization or for investigating a ligand's mechanism of action. Advances in computational methods, including both physics-based and machine learning approaches, as well as in complementary experimental techniques, are making docking an even more powerful tool. We review how docking works and how it can drive drug discovery and biological research. We also describe its current limitations and ongoing efforts to overcome them.

分子对接已成为结构生物学家和药物化学家工具包中不可或缺的一部分。给定化合物和分子靶标（例如蛋白质）的三维结构，对接方法就能将化合物与靶标结合，预测化合物的结合结构和结合能。通过筛选大型虚拟化合物库，对接法可用于发现靶标的新型配体。对接还可以为基于结构的配体优化或配体作用机制的研究提供一个有用的起点。计算方法（包括基于物理的方法和机器学习方法）以及补充实验技术的进步正在使对接成为一种更加强大的工具。我们回顾了对接的工作原理以及它如何推动药物发现和生物研究。我们还介绍了对接目前存在的局限性以及为克服这些局限性所做的不懈努力。

引用次数: 0

How Natural Enzymes and Synthetic Ribozymes Generate Methylated Nucleotides in RNA 天然酶和合成核糖酶如何在 RNA 中生成甲基化核苷酸

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2024-04-10 DOI: 10.1146/annurev-biochem-030222-112310

Claudia Höbartner, Katherine E. Bohnsack, Markus T. Bohnsack

Methylation of RNA nucleotides represents an important layer of gene expression regulation, and perturbation of the RNA methylome is associated with pathophysiology. In cells, RNA methylations are installed by RNA methyltransferases (RNMTs) that are specialized to catalyze particular types of methylation (ribose or different base positions). Furthermore, RNMTs must specifically recognize their appropriate target RNAs within the RNA-dense cellular environment. Some RNMTs are catalytically active alone and achieve target specificity via recognition of sequence motifs and/or RNA structures. Others function together with protein cofactors that can influence stability, S-adenosyl-L-methionine binding, and RNA affinity as well as aiding specific recruitment and catalytic activity. Association of RNMTs with guide RNAs represents an alternative mechanism to direct site-specific methylation by an RNMT that lacks intrinsic specificity. Recently, ribozyme-catalyzed methylation of RNA has been achieved in vitro, and here, we compare these different strategies for RNA methylation from structural and mechanistic perspectives.

RNA 核苷酸的甲基化是基因表达调控的一个重要层面，RNA 甲基组的干扰与病理生理学有关。在细胞中，RNA 甲基化由专门催化特定类型甲基化（核糖或不同碱基位置）的 RNA 甲基转移酶（RNMTs）完成。此外，RNMTs 还必须在 RNA 密集的细胞环境中特异性地识别适当的目标 RNA。一些 RNMTs 可单独发挥催化作用，并通过识别序列基序和/或 RNA 结构实现目标特异性。其他 RNMTs 则与蛋白质辅助因子一起发挥作用，这些辅助因子可影响稳定性、S-腺苷-L-蛋氨酸结合力和 RNA 亲和力，并有助于特异性招募和催化活性。RNMT 与引导 RNA 的结合是 RNMT 直接进行特定位点甲基化的另一种机制，它缺乏内在的特异性。最近，人们在体外实现了核糖酶催化的 RNA 甲基化，在此，我们从结构和机理的角度对这些不同的 RNA 甲基化策略进行了比较。

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引用次数: 0

Natural and Engineered Guide RNA–directed Transposition with CRISPR-Associated Tn7-like Transposons 利用 CRISPR 相关 Tn7 类转座子进行天然和工程化的引导 RNA 定向转座

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2024-04-10 DOI: 10.1146/annurev-biochem-030122-041908

Shan-Chi Hsieh, Joseph E. Peters

CRISPR–Cas (clustered regularly interspaced short palindromic repeats–CRISPR-associated nuclease) defense systems have been naturally coopted for guide RNA–directed transposition on multiple occasions. In all cases, cooption occurred with diverse elements related to the bacterial transposon Tn7. Tn7 tightly controls transposition; the transposase is activated only when special targets are recognized by dedicated target-site selection proteins. Tn7 and the Tn7-like elements that coopted CRISPR–Cas systems evolved complementary targeting pathways: one that recognizes a highly conserved site in the chromosome and a second pathway that targets mobile plasmids capable of cell-to-cell transfer. Tn7 and Tn7-like elements deliver a single integration into the site they recognize and also control the orientation of the integration event, providing future potential for use as programmable gene-integration tools. Early work has shown that guide RNA–directed transposition systems can be adapted to diverse hosts, even within microbial communities, suggesting great potential for engineering these systems as powerful gene-editing tools.

CRISPR-Cas（簇状有规律间隔短回文重复序列-CRISPR相关核酸酶）防御系统曾多次被自然合作用于引导RNA定向转座。在所有这些案例中，共同作用都发生在与细菌转座子 Tn7 有关的不同元件上。Tn7 严格控制转座；只有当专用的目标位点选择蛋白识别到特殊目标时，转座酶才会被激活。Tn7 和与 CRISPR-Cas 系统共用的 Tn7 类似元件进化出了互补的靶向途径：一个途径识别染色体中的高度保守位点，另一个途径靶向能够在细胞间转移的移动质粒。Tn7 和 Tn7-like 元件能将单个整合体整合到它们所识别的位点，还能控制整合事件的方向，为未来用作可编程基因整合工具提供了潜力。早期的研究表明，RNA引导的转座系统可以适应不同的宿主，甚至是微生物群落，这表明这些系统作为强大的基因编辑工具具有巨大的工程潜力。

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引用次数: 0

The Story of RNA Unfolded: The Molecular Function of DEAD- and DExH-Box ATPases and Their Complex Relationship with Membraneless Organelles RNA 展开的故事：DEAD-和DExH-Box ATP酶的分子功能及其与无膜细胞器的复杂关系

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2024-04-10 DOI: 10.1146/annurev-biochem-052521-121259

Kerstin Dörner, Maria Hondele

DEAD- and DExH-box ATPases (DDX/DHXs) are abundant and highly conserved cellular enzymes ubiquitously involved in RNA processing. By remodeling RNA–RNA and RNA–protein interactions, they often function as gatekeepers that control the progression of diverse RNA maturation steps. Intriguingly, most DDX/DHXs localize to membraneless organelles (MLOs) such as nucleoli, nuclear speckles, stress granules, or processing bodies. Recent findings suggest not only that localization to MLOs can promote interaction between DDX/DHXs and their targets but also that DDX/DHXs are key regulators of MLO formation and turnover through their condensation and ATPase activity. In this review, we describe the molecular function of DDX/DHXs in ribosome biogenesis, messenger RNA splicing, export, translation, and storage or decay as well as their association with prominent MLOs. We discuss how the enzymatic function of DDX/DHXs in RNA processing is linked to DDX/DHX condensation, the accumulation of ribonucleoprotein particles and MLO dynamics. Future research will reveal how these processes orchestrate the RNA life cycle in MLO space and DDX/DHX time.

DEAD- 和 DExH-box ATPases（DDX/DHXs）是一种丰富且高度保守的细胞酶，普遍参与 RNA 处理。通过重塑 RNA-RNA 和 RNA 蛋白之间的相互作用，它们通常起着看门人的作用，控制着各种 RNA 成熟步骤的进展。耐人寻味的是，大多数 DDX/DHX 定位于核小体、核斑点、应激颗粒或加工体等无膜细胞器（MLO）。最近的研究结果表明，定位于 MLOs 不仅能促进 DDX/DHX 与其靶标之间的相互作用，而且 DDX/DHX 还能通过其缩聚和 ATPase 活性成为 MLO 形成和周转的关键调节因子。在这篇综述中，我们描述了 DDX/DHXs 在核糖体生物发生、信使 RNA 剪接、输出、翻译和储存或衰变中的分子功能，以及它们与重要 MLO 的关联。我们讨论了 DDX/DHXs 在 RNA 加工中的酶功能如何与 DDX/DHX 缩合、核糖核蛋白颗粒的积累和 MLO 的动力学联系在一起。未来的研究将揭示这些过程如何在 MLO 空间和 DDX/DHX 时间内协调 RNA 生命周期。

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引用次数: 0

The Endo-Lysosomal Damage Response 内溶酶体损伤反应

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2024-04-10 DOI: 10.1146/annurev-biochem-030222-102505

Hemmo Meyer, Bojana Kravic

Lysosomes are the degradative endpoints of material delivered by endocytosis and autophagy and are therefore particularly prone to damage. Membrane permeabilization or full rupture of lysosomal or late endosomal compartments is highly deleterious because it threatens cellular homeostasis and can elicit cell death and inflammatory signaling. Cells have developed a complex response to endo-lysosomal damage that largely consists of three branches. Initially, a number of repair pathways are activated to restore the integrity of the lysosomal membrane. If repair fails or if damage is too extensive, lysosomes are isolated and degraded by a form of selective autophagy termed lysophagy. Meanwhile, an mTORC1-governed signaling cascade drives biogenesis and regeneration of new lysosomal components to reestablish the full lysosomal capacity of the cell. This damage response is vital to counteract the effects of various conditions, including neurodegeneration and infection, and can constitute a critical vulnerability in cancer cells.

溶酶体是内吞和自噬所传递物质的降解终点，因此特别容易受到损伤。溶酶体或晚期内体区室的膜渗透或完全破裂是非常有害的，因为它威胁到细胞的稳态，并可能引起细胞死亡和炎症信号传导。细胞对内溶酶体损伤做出了复杂的反应，主要包括三个分支。最初，一些修复途径被激活，以恢复溶酶体膜的完整性。如果修复失败或损伤范围过大，溶酶体就会被分离出来，并通过一种被称为溶酶体吞噬的选择性自噬形式被降解。与此同时，由 mTORC1 控制的信号级联会驱动新溶酶体成分的生物生成和再生，以重建细胞的全部溶酶体能力。这种损伤反应对于抵消神经变性和感染等各种情况的影响至关重要，也可能成为癌细胞的一个关键弱点。

引用次数: 0

Structural Biochemistry of Muscle Contraction. 肌肉收缩的结构生物化学。

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2023-06-20 DOI: 10.1146/annurev-biochem-052521-042909

Zhexin Wang, Stefan Raunser

Muscles are essential for movement and heart function. Contraction and relaxation of muscles rely on the sliding of two types of filaments-the thin filament and the thick myosin filament. The thin filament is composed mainly of filamentous actin (F-actin), tropomyosin, and troponin. Additionally, several other proteins are involved in the contraction mechanism, and their malfunction can lead to diverse muscle diseases, such as cardiomyopathies. We review recent high-resolution structural data that explain the mechanism of action of muscle proteins at an unprecedented level of molecular detail. We focus on the molecular structures of the components of the thin and thick filaments and highlight the mechanisms underlying force generation through actin-myosin interactions, as well as Ca²⁺-dependent regulation via the dihydropyridine receptor, the ryanodine receptor, and troponin. We particularly emphasize the impact of cryo-electron microscopy and cryo-electron tomography in leading muscle research into a new era.

肌肉对运动和心脏功能至关重要。肌肉的收缩和松弛依赖于两种纤维的滑动——细纤维和粗肌球蛋白纤维。细丝主要由丝状肌动蛋白(F-actin)、原肌球蛋白和肌钙蛋白组成。此外，其他几种蛋白质也参与收缩机制，它们的功能障碍可导致多种肌肉疾病，如心肌病。我们回顾了最近的高分辨率结构数据，这些数据在前所未有的分子细节水平上解释了肌肉蛋白的作用机制。我们专注于细纤维和粗纤维成分的分子结构，并强调通过肌动蛋白-肌球蛋白相互作用产生力的机制，以及通过二氢吡啶受体、红嘌呤受体和肌钙蛋白进行的Ca2+依赖性调节。我们特别强调低温电子显微镜和低温电子断层扫描在引领肌肉研究进入新时代的影响。

引用次数: 3

Transcription-Coupled Nucleotide Excision Repair and the Transcriptional Response to UV-Induced DNA Damage. 转录偶联核苷酸切除修复和紫外线诱导DNA损伤的转录反应。

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Annual review of biochemistry

Pub Date : 2023-06-20 DOI: 10.1146/annurev-biochem-052621-091205

Nicolás Nieto Moreno, Anouk M Olthof, Jesper Q Svejstrup

Ultraviolet (UV) irradiation and other genotoxic stresses induce bulky DNA lesions, which threaten genome stability and cell viability. Cells have evolved two main repair pathways to remove such lesions: global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The modes by which these subpathways recognize DNA lesions are distinct, but they converge onto the same downstream steps for DNA repair. Here, we first summarize the current understanding of these repair mechanisms, specifically focusing on the roles of stalled RNA polymerase II, Cockayne syndrome protein B (CSB), CSA and UV-stimulated scaffold protein A (UVSSA) in TC-NER. We also discuss the intriguing role of protein ubiquitylation in this process. Additionally, we highlight key aspects of the effect of UV irradiation on transcription and describe the role of signaling cascades in orchestrating this response. Finally, we describe the pathogenic mechanisms underlying xeroderma pigmentosum and Cockayne syndrome, the two main diseases linked to mutations in NER factors.

紫外线(UV)照射和其他基因毒性应激可诱导大量DNA损伤，从而威胁到基因组的稳定性和细胞的活力。细胞已经进化出两种主要的修复途径来去除这些病变:全球基因组核苷酸切除修复(GG-NER)和转录偶联核苷酸切除修复(TC-NER)。这些亚通路识别DNA损伤的模式是不同的，但它们汇聚到DNA修复的相同下游步骤。在这里，我们首先总结了目前对这些修复机制的理解，特别关注了停滞RNA聚合酶II、Cockayne综合征蛋白B (CSB)、CSA和uv刺激支架蛋白A (uvsa)在TC-NER中的作用。我们还讨论了蛋白质泛素化在这一过程中的有趣作用。此外，我们强调了紫外线照射对转录影响的关键方面，并描述了信号级联在协调这种反应中的作用。最后，我们描述了色素干皮病和Cockayne综合征的致病机制，这两种主要疾病与NER因子突变有关。

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引用次数: 6

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