Journal of Molecular Biology最新文献_第9页

The Influence of Phosphoinositide Lipids in the Molecular Biology of Membrane Proteins: Recent Insights from Simulations 磷脂肌醇脂在膜蛋白分子生物学中的影响：来自模拟的最新见解。

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-09 DOI: 10.1016/j.jmb.2025.168937

George Hedger , Hsin-Yung Yen

The phosphoinositide family of membrane lipids play diverse and critical roles in eukaryotic molecular biology. Much of this biological activity derives from interactions of phosphoinositide lipids with integral and peripheral membrane proteins, leading to modulation of protein structure, function, and cellular distribution. Since the discovery of phosphoinositides in the 1940s, combined molecular biology, biophysical, and structural approaches have made enormous progress in untangling this vast and diverse cellular network of interactions. More recently, in silico approaches such as molecular dynamics simulations have proven to be an asset in prospectively identifying, characterising, explaining the structural basis of these interactions, and in the best cases providing atomic level testable hypotheses on how such interactions control the function of a given membrane protein. This review details a number of recent seminal discoveries in phosphoinositide biology, enabled by advanced biomolecular simulation, and its integration with molecular biology, biophysical, and structural biology approaches. The results of the simulation studies agree well with experimental work, and in a number of notable cases have arrived at the key conclusion several years in advance of the experimental structures.

Summary

Hedger and Yen review developments in simulations of phosphoinositides and membrane proteins.

膜脂磷脂肌肽家族在真核生物分子生物学中发挥着多样而关键的作用。这种生物活性大部分来源于磷脂肌肽脂与整体和外周膜蛋白的相互作用，导致蛋白质结构、功能和细胞分布的调节。自20世纪40年代发现磷酸肌苷以来，结合分子生物学、生物物理学和结构方法，在解开这个庞大而多样的相互作用细胞网络方面取得了巨大进展。最近，分子动力学模拟等计算机方法已被证明是前瞻性识别、表征和解释这些相互作用的结构基础的一种资产，并且在最好的情况下，提供了关于这些相互作用如何控制给定膜蛋白功能的原子水平可测试的假设。这篇综述详细介绍了磷肌苷生物学最近的一些重大发现，这些发现是由先进的生物分子模拟技术实现的，并与分子生物学、生物物理学和结构生物学方法相结合。模拟研究的结果与实验结果吻合得很好，并且在一些值得注意的情况下，已经比实验结构提前几年得出了关键结论。摘要：Hedger和Yen回顾了磷酸肌苷和膜蛋白的模拟研究进展。

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引用次数: 0

transCAE: Enhancing Cell Type Annotation in Single-cell RNA-seq Data with Transfer Learning and Convolutional Autoencoder transCAE：利用迁移学习和卷积自编码器增强单细胞RNA-seq数据的细胞类型注释。

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-09 DOI: 10.1016/j.jmb.2025.168936

Qingchun Liu, Yan Xu

Single-cell RNA sequencing (scRNA-seq) analysis offers tremendous potential for addressing various biological questions, with one key application being the annotation of query datasets with unknown cell types using well-annotated external reference datasets. However, the performance of existing supervised or semi-supervised methods largely depends on the quality of source data. Furthermore, these methods often struggle with the batch effects arising from different platforms when handling multiple reference or query datasets, making precise annotation challenging. We developed transCAE, a robust transfer learning-based algorithm for single-cell annotation that integrates unsupervised dimensionality reduction with supervised cell type classification. This approach fully leverages information from both reference and query datasets to achieve precise cell classification within the query data. Extensive evaluations show that transCAE significantly enhances classification accuracy and efficiently mitigates batch effects. Compared to other state-of-the-art methods, transCAE demonstrates superior performance in experiments involving multiple reference or query datasets. These strengths position transCAE as an optimal annotation method for scRNA-seq datasets.

单细胞RNA测序（scRNA-seq）分析为解决各种生物学问题提供了巨大的潜力，其中一个关键应用是使用注释良好的外部参考数据集对未知细胞类型的查询数据集进行注释。然而，现有的监督或半监督方法的性能在很大程度上取决于源数据的质量。此外，当处理多个引用或查询数据集时，这些方法经常与不同平台产生的批处理效果作斗争，这使得精确注释变得困难。我们开发了transCAE，这是一种基于迁移学习的鲁棒单细胞注释算法，它集成了无监督降维和监督细胞类型分类。这种方法充分利用来自参考和查询数据集的信息，在查询数据中实现精确的单元格分类。广泛的评估表明，transCAE显著提高了分类精度，有效地缓解了批处理效应。与其他最先进的方法相比，transCAE在涉及多个参考或查询数据集的实验中表现出优越的性能。这些优势使transCAE成为scRNA-seq数据集的最佳注释方法。

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引用次数: 0

Molecular Basis of Interchain Disulfide Bond Formation in BMP-9 and BMP-10 BMP-9和BMP-10中链间二硫键形成的分子基础。

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-08 DOI: 10.1016/j.jmb.2025.168935

Tristin A. Schwartze , Stefanie A. Morosky , Teresa L. Rosato , Amy Henrickson , Guowu Lin , Cynthia S. Hinck , Alexander B. Taylor , Shaun K. Olsen , Guillermo Calero , Borries Demeler , Beth L. Roman , Andrew P. Hinck

BMP-9 and BMP-10 are TGF-β family signaling ligands naturally secreted into blood. They act on endothelial cells and are required for proper development and maintenance of the vasculature. In hereditary hemorrhagic telangiectasia, regulation is disrupted due to mutations in the BMP-9/10 pathway, namely in the type I receptor ALK1 or the co-receptor endoglin. It has been demonstrated that BMP-9/10 heterodimers are the most abundant signaling species in the blood, but it is unclear how they form. Unlike other ligands of the TGF-β family, BMP-9 and -10 are secreted as a mixture of disulfide-linked dimers and monomers, in which the interchain cysteine (Cys-392) remains either paired or unpaired. Here, we show that the monomers are secreted in a cysteinylated form that crystallizes as a non-covalent dimer. Despite this, monomers do not self-associate at micromolar or lower concentrations and have reduced signaling potency compared to disulfide-linked dimers. We further show using protein crystallography that the interchain disulfide of the BMP-9 homodimer adopts a highly strained syn-periplanar conformation. Hence, geometric strain across the interchain disulfide is responsible for infrequent interchain disulfide bond formation, not the cysteinylation. Additionally, we show that interchain disulfide bond formation occurs less in BMP-9 than BMP-10 and these frequencies can be reversed by swapping residues near the interchain disulfide that form attractive interactions with the opposing protomer. Finally, we discuss the implications of these observations on BMP-9/10 heterodimer formation.

BMP-9和BMP-10是TGF-β家族天然分泌到血液中的信号配体。它们作用于内皮细胞，是血管系统正常发育和维持所必需的。在遗传性出血性毛细血管扩张中，由于BMP-9/10通路的突变，即I型受体ALK1或协同受体内啡肽的突变，调节被破坏。已经证明，BMP-9/10异二聚体是血液中最丰富的信号物种，但尚不清楚它们是如何形成的。与TGF-β家族的其他配体不同，BMP-9和bmp -10以二硫连接的二聚体和单体的混合物分泌，其中链间半胱氨酸（Cys-392）保持未配对或配对。在这里，我们发现这些单体以半胱氨酸化的形式分泌，结晶为非共价二聚体。尽管如此，单体在微摩尔或更低的浓度下不能自缔合，与二硫化物连接的二聚体相比，其信号效力降低。我们进一步使用蛋白质晶体学表明，BMP-9同型二聚体的链间二硫化物采用高度应变的顺平面构象。因此，跨二硫链的几何应变是导致不常见的二硫链间键形成的原因，而不是半胱氨酸化。此外，我们发现BMP-9中链间二硫键的形成比BMP-10少，这些频率可以通过交换链间二硫附近的残基来逆转，这些残基与相反的原聚物形成吸引相互作用。最后，我们讨论了这些观察结果对BMP-9/10异源二聚体形成的影响。

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引用次数: 0

Studying the Function of tRNA Modifications: Experimental Challenges and Opportunities. tRNA修饰功能研究：实验挑战与机遇

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-03 DOI: 10.1016/j.jmb.2024.168934

Maria Kompatscher, Isabell Gonnella, Matthias Erlacher

tRNAs are essential molecules in protein synthesis, responsible for translating the four-nucleotide genetic code into the corresponding amino acid sequence. RNA modifications play a crucial role in influencing tRNA folding, structure, and function. These modifications, ranging from simple methylations to complex hypermodified species, are distributed throughout the tRNA molecule. Depending on their type and position, they contribute to the accuracy and efficiency of decoding by participating in a complex network of interactions. The enzymatic processes introducing these modifications are equally intricate and diverse, adding further complexity. As a result, studying tRNA modifications faces limitations at multiple levels. This review addresses the challenges involved in manipulating and studying the function of tRNA modifications and discusses experimental strategies and possibilities to overcome these obstacles.

trna是蛋白质合成中必不可少的分子，负责将四核苷酸遗传密码翻译成相应的氨基酸序列。RNA修饰在影响tRNA折叠、结构和功能方面起着至关重要的作用。这些修饰，从简单的甲基化到复杂的超修饰，分布在整个tRNA分子中。根据它们的类型和位置，它们通过参与复杂的相互作用网络来促进解码的准确性和效率。引入这些修饰的酶促过程同样复杂多样，进一步增加了复杂性。因此，对tRNA修饰的研究在多个层面上都面临着限制。本文综述了操纵和研究tRNA修饰功能所面临的挑战，并讨论了克服这些障碍的实验策略和可能性。

引用次数: 0

The RNA-Binding Properties of Annexins 膜联蛋白的rna结合特性。

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-02 DOI: 10.1016/j.jmb.2024.168933

Gian Gaetano Tartaglia , Hanne Hollås , Bjarte Håvik , Anni Vedeler , Annalisa Pastore

Annexins are a family of calcium-dependent phospholipid-binding proteins involved in crucial cellular processes such as cell division, calcium signaling, vesicle trafficking, membrane repair, and apoptosis. In addition to these properties, Annexins have also been shown to bind RNA, although this function is not universally recognized. In the attempt to clarify this important issue, we employed an integrated combination of experimental and computational approaches. Using the catRAPID algorithm, we accurately predicted known RNA-binding partners of Annexins, supported by experimental validation. We then constructed a virtual library of potential mRNA partners for Annexin A2, identifying regions within its structure directly involved in RNA binding. Beyond RNA interaction, some Annexins, notably AnxA7 and AnxA11, exhibit strong phase separation tendencies driven by their N-termini. These biophysical properties likely play roles in RNA trafficking and localization particularly in neurons, where they may influence processes such as synaptic plasticity, learning, and memory. Our predictions contribute to a deeper understanding of the Annexin function, emphasizing their potential impact on RNA regulation and cellular compartmentalization through phase separation and propose a powerful computational tool for the prediction of RNA-binding properties.

膜联蛋白是一个钙依赖性磷脂结合蛋白家族，参与关键的细胞过程，如细胞分裂、钙信号传导、囊泡运输、膜修复和凋亡。除了这些特性外，膜联蛋白还被证明可以结合RNA，尽管这种功能尚未得到普遍认可。为了澄清这一重要问题，我们采用了实验和计算方法的综合结合。使用catRAPID算法，我们准确地预测了已知的膜联蛋白的rna结合伙伴，并得到了实验验证。然后，我们构建了一个潜在的膜联蛋白A2 mRNA伴侣的虚拟文库，确定其结构中直接参与RNA结合的区域。除了RNA相互作用外，一些膜联蛋白，特别是AnxA7和AnxA11，表现出由其n端驱动的强相分离倾向。这些生物物理特性可能在RNA运输和定位中发挥作用，特别是在神经元中，它们可能影响突触可塑性、学习和记忆等过程。我们的预测有助于更深入地了解膜联蛋白的功能，强调它们通过相分离对RNA调控和细胞区隔化的潜在影响，并为预测RNA结合特性提供了一个强大的计算工具。

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引用次数: 0

Context-Dependent and Locus-Specific Role of H3K36 Methylation in Transcriptional Regulation H3K36 甲基化在转录调控中的上下文依赖性和基因座特异性作用

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-01 DOI: 10.1016/j.jmb.2024.168796

Min Kyung Lee , Na Hyun Park , Soo Young Lee, TaeSoo Kim

H3K36 methylation is a critical histone modification involved in transcription regulation. It involves the mono (H3K36me1), di (H3K36me2), and/or tri-methylation (H3K36me3) of lysine 36 on histone H3 by methyltransferases. In yeast, Set2 catalyzes all three methylation states. By contrast, in higher eukaryotes, at least eight methyltransferases catalyze different methylation states, including SETD2 for H3K36me3 and the NSD family for H3K36me2 in vivo. Both Set2 and SETD2 interact with the phosphorylated CTD of RNA Pol II, which links H3K36 methylation to transcription. In yeast, H3K36me3 and H3K36me2 peak at the 3′ ends of genes. In higher eukaryotes, this is also true for H3K36me3 but not for H3K36me2, which is enriched at the 5′ ends of genes and intergenic regions, suggesting that H3K36me2 and H3K36me3 may play different regulatory roles. Whether H3K36me1 demonstrates preferential distribution remains unclear. H3K36me3 is essential for inhibiting transcription elongation. It also suppresses cryptic transcription by promoting histone deacetylation by the histone deacetylases Rpd3S (yeast) and variant NuRD (higher eukaryotes). H3K36me3 also facilitates DNA methylation by DNMT3B, thereby preventing spurious transcription initiation. H3K36me3 not only represses transcription since it promotes the activation of mRNA and cryptic promoters in response to environmental changes by targeting the histone acetyltransferase NuA3 in yeast. Further research is needed to elucidate the methylation state- and locus-specific functions of H3K36me1 and the mechanisms that regulate it.

H3K36 甲基化是参与转录调控的一种关键组蛋白修饰。它包括通过甲基转移酶对组蛋白 H3 上的赖氨酸 36 进行单甲基化（H3K36me1）、双甲基化（H3K36me2）和/或三甲基化（H3K36me3）。在酵母中，Set2 催化所有三种甲基化状态。相比之下，在高等真核生物中，至少有八种甲基转移酶能催化不同的甲基化状态，其中包括在体内催化 H3K36me3 的 SETD2 和催化 H3K36me2 的 NSD 家族。Set2 和 SETD2 都与 RNA Pol II 的磷酸化 CTD 相互作用，从而将 H3K36 甲基化与转录联系起来。在酵母中，H3K36me3 和 H3K36me2 在基因的 3' 端达到峰值。在高等真核生物中，H3K36me3 的情况也是如此，但 H3K36me2 的情况却并非如此，H3K36me2 富集在基因的 5'末端和基因间区域，这表明 H3K36me2 和 H3K36me3 可能发挥着不同的调控作用。H3K36me1是否会优先分布仍不清楚。H3K36me3 对抑制转录延伸至关重要。它还通过促进组蛋白去乙酰化酶 Rpd3S（酵母）和变体 NuRD（高等真核生物）的组蛋白去乙酰化作用来抑制隐性转录。H3K36me3 还有助于 DNMT3B 进行 DNA 甲基化，从而防止错误的转录启动。H3K36me3 不仅能抑制转录，还能通过靶向酵母中的组蛋白乙酰转移酶 NuA3 促进 mRNA 和隐性启动子的激活，以应对环境变化。要阐明H3K36me1的甲基化状态和位点特异性功能及其调控机制，还需要进一步的研究。

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引用次数: 0

NusG–Spt5 Transcription Factors: Universal, Dynamic Modulators of Gene Expression NusG-Spt5 转录因子：基因表达的通用动态调节因子

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-01 DOI: 10.1016/j.jmb.2024.168814

Rachel A. Mooney , Junqiao Zhu , Jason Saba , Robert Landick

The accurate and efficient biogenesis of RNA by cellular RNA polymerase (RNAP) requires accessory factors that regulate the initiation, elongation, and termination of transcription. Of the many discovered to date, the elongation regulator NusG–Spt5 is the only universally conserved transcription factor. With orthologs and paralogs found in all three domains of life, this ubiquity underscores their ancient and essential regulatory functions. NusG–Spt5 proteins evolved to maintain a similar binding interface to RNAP through contacts of the NusG N-terminal domain (NGN) that bridge the main DNA-binding cleft. We propose that varying strength of these contacts, modulated by tethering interactions, either decrease transcriptional pausing by smoothing the rugged thermodynamic landscape of transcript elongation or enhance pausing, depending on which conformation of RNAP is stabilized by NGN contacts. NusG–Spt5 contains one (in bacteria and archaea) or more (in eukaryotes) C-terminal domains that use a KOW fold to contact diverse targets, tether the NGN, and control RNA biogenesis. Recent work highlights these diverse functions in different organisms. Some bacteria contain multiple specialized NusG paralogs that regulate subsets of operons via sequence-specific targeting, controlling production of antibiotics, toxins, or capsule proteins. Despite their common origin, NusG orthologs can differ in their target selection, interacting partners, and effects on RNA synthesis. We describe the current understanding of NusG–Spt5 structure, interactions with RNAP and other regulators, and cellular functions including significant recent progress from genome-wide analyses, single-molecule visualization, and cryo-EM. The recent findings highlight the remarkable diversity of function among these structurally conserved proteins.

细胞 RNA 聚合酶（RNAP）准确而高效地生物合成 RNA 需要辅助因子来调节转录的启动、延伸和终止。在迄今发现的众多转录因子中，延伸调节因子 NusG-Spt5 是唯一一种普遍保守的转录因子。在生命的所有三个领域都发现了其直系同源物和旁系同源物，这种普遍性强调了它们古老而重要的调控功能。NusG-Spt5 蛋白在进化过程中通过 NusG N 端结构域（NGN）的接触保持了与 RNAP 相似的结合界面，NGN 在主要的 DNA 结合裂隙之间架起了桥梁。我们认为，这些接触的不同强度受系链相互作用的调节，要么通过平滑转录本伸长的崎岖热力学景观来减少转录暂停，要么根据 NGN 接触所稳定的 RNAP 构象来增强暂停。NusG-Spt5 包含一个（在细菌和古生菌中）或多个（在真核生物中）C-末端结构域，这些结构域利用 KOW 折叠来接触不同的靶标、拴系 NGN 并控制 RNA 的生物发生。最近的研究突显了不同生物体的这些不同功能。一些细菌含有多个特化的 NusG 旁系亲属，它们通过序列特异性靶向调节操作子子集，控制抗生素、毒素或囊蛋白的产生。尽管 NusG 同源物具有共同的起源，但它们在靶标选择、相互作用伙伴以及对 RNA 合成的影响方面可能存在差异。我们描述了目前对 NusG-Spt5 结构、与 RNAP 和其他调控因子的相互作用以及细胞功能的理解，包括最近在全基因组分析、单分子可视化和低温电子显微镜方面取得的重大进展。最近的研究结果突显了这些结构上保守的蛋白质在功能上的显著多样性。

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引用次数: 0

Chromatin Transcription Elongation – A Structural Perspective 染色质转录延伸--结构视角。

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-01 DOI: 10.1016/j.jmb.2024.168845

Lucas Farnung

In eukaryotic cells, transcription by RNA polymerase II occurs in the context of chromatin, requiring the transcription machinery to navigate through nucleosomes as it traverses gene bodies. Recent advances in structural biology have provided unprecedented insights into the mechanisms underlying transcription elongation. This review presents a structural perspective on transcription through chromatin, focusing on the latest findings from high-resolution structures of transcribing RNA polymerase II-nucleosome complexes. I discuss how RNA polymerase II, in concert with elongation factors such as SPT4/5, SPT6, ELOF1, and the PAF1 complex, engages with and transcribes through nucleosomes. The review examines the stepwise unwrapping of nucleosomal DNA as polymerase advances, the roles of elongation factors in facilitating this process, and the mechanisms of nucleosome retention and transfer during transcription. This structural perspective provides a foundation for understanding the intricate interplay between the transcription machinery and chromatin, offering insights into how cells balance the need for genetic accessibility with the maintenance of genome stability and epigenetic regulation.

在真核细胞中，RNA聚合酶II的转录是在染色质背景下进行的，转录机器在穿越基因体时需要穿过核小体。结构生物学的最新进展让人们对转录伸长的内在机制有了前所未有的深入了解。这篇综述从结构的角度阐述了通过染色质进行转录的问题，重点是转录 RNA 聚合酶 II-核小体复合物高分辨率结构的最新发现。我将讨论 RNA 聚合酶 II 如何与 SPT4/5、SPT6、ELOF1 和 PAF1 复合物等延伸因子协同作用，并通过核小体进行转录。这篇综述探讨了随着聚合酶的推进，核糖体 DNA 逐步解开的过程、延伸因子在促进这一过程中的作用，以及转录过程中核糖体保留和转移的机制。这一结构性视角为理解转录机制与染色质之间错综复杂的相互作用奠定了基础，有助于深入了解细胞如何在遗传可及性需求与维持基因组稳定性和表观遗传调控之间取得平衡。

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引用次数: 0

The CDK9-SPT5 Axis in Control of Transcription Elongation by RNAPII CDK9-SPT5 轴控制 RNAPII 的转录延伸。

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-01 DOI: 10.1016/j.jmb.2024.168746

Rui Sun, Robert P. Fisher

The RNA polymerase II (RNAPII) transcription cycle is regulated at every stage by a network of cyclin-dependent protein kinases (CDKs) and protein phosphatases. Progression of RNAPII from initiation to termination is marked by changing patterns of phosphorylation on the highly repetitive carboxy-terminal domain (CTD) of RPB1, its largest subunit, suggesting the existence of a CTD code. In parallel, the conserved transcription elongation factor SPT5, large subunit of the DRB sensitivity-inducing factor (DSIF), undergoes spatiotemporally regulated changes in phosphorylation state that may be directly linked to the transitions between transcription-cycle phases. Here we review insights gained from recent structural, biochemical, and genetic analyses of human SPT5, which suggest that two of its phosphorylated regions perform distinct functions at different points in transcription. Phosphorylation within a flexible, RNA-binding linker promotes release from the promoter-proximal pause—frequently a rate-limiting step in gene expression—whereas modifications in a repetitive carboxy-terminal region are thought to favor processive elongation, and are removed just prior to termination. Phosphorylations in both motifs depend on CDK9, catalytic subunit of positive transcription elongation factor b (P-TEFb); their different timing of accumulation on chromatin and function during the transcription cycle might reflect their removal by different phosphatases, different kinetics of phosphorylation by CDK9, or both. Perturbations of SPT5 regulation have profound impacts on viability and development in model organisms through largely unknown mechanisms, while enzymes that modify SPT5 have emerged as potential therapeutic targets in cancer; elucidating a putative SPT5 code is therefore a high priority.

RNA 聚合酶 II（RNAPII）转录周期的每个阶段都受到依赖细胞周期蛋白的蛋白激酶（CDK）和蛋白磷酸酶网络的调控。RNAPII 从起始到终止的过程中，其最大亚基 RPB1 高度重复的羧基末端结构域（CTD）上的磷酸化模式不断变化，这表明存在 CTD 代码。与此同时，保守的转录延伸因子 SPT5（DRB 敏感性诱导因子（DSIF）的大亚基）也会发生时空调控的磷酸化状态变化，这种变化可能与转录周期阶段之间的转换直接相关。在此，我们回顾了最近对人类 SPT5 进行的结构、生化和遗传分析所获得的启示，这些分析表明其两个磷酸化区域在转录的不同阶段发挥着不同的功能。在一个灵活的 RNA 结合连接点上的磷酸化促进了从启动子-近端暂停中的释放--这通常是基因表达的限速步骤--而在一个重复的羧基末端区域的修饰被认为有利于过程性延伸，并在终止前被去除。这两个基团的磷酸化都依赖于正转录延伸因子 b（P-TEFb）的催化亚基 CDK9；它们在染色质上积累的时间和在转录周期中的功能不同，可能反映了它们被不同的磷酸酶清除、CDK9 磷酸化的动力学不同或两者兼而有之。SPT5调控的干扰会对模式生物的生存和发育产生深远影响，其机制尚不清楚，而修饰SPT5的酶已成为癌症的潜在治疗靶标；因此，阐明SPT5的推定密码是当务之急。

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引用次数: 0

Fateful Decisions of Where to Cut the Line: Pathology Associated with Aberrant 3′ End Processing and Transcription Termination 决定在何处切断转录线的致命决定：与 3'末端异常处理和转录终止有关的病理学。

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology

Pub Date : 2025-01-01 DOI: 10.1016/j.jmb.2024.168802

Pawel Grzechnik , Hannah E Mischo

Aberrant gene expression lies at the heart of many pathologies. This review will point out how 3′ end processing, the final mRNA-maturation step in the transcription cycle, is surprisingly prone to regulated as well as stochastic variations with a wide range of consequences. Whereas smaller variations contribute to the plasticity of gene expression, larger alternations to 3′ end processing and coupled transcription termination can lead to pathological consequences. These can be caused by the local mutation of one gene or affect larger numbers of genes systematically, if aspects of the mechanisms of 3′ end processing and transcription termination are altered.

基因表达异常是许多病症的核心所在。这篇综述将指出转录周期中最后一个 mRNA 成熟步骤--3'末端处理--是如何出人意料地容易发生调节性和随机性变化，从而产生广泛的后果。较小的变化有助于基因表达的可塑性，而较大的 3'末端处理和转录终止耦合变化则可能导致病理后果。如果 3'末端处理和转录终止机制的某些方面发生变化，这些变化可能由一个基因的局部突变引起，也可能系统地影响更多的基因。

引用次数: 0