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Long Noncoding RNAs: Molecular Modalities to Organismal Functions. 长链非编码rna:生物体功能的分子模式。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-06-20 DOI: 10.1146/annurev-biochem-062917-012708
John L Rinn, Howard Y Chang

We have known for decades that long noncoding RNAs (lncRNAs) can play essential functions across most forms of life. The maintenance of chromosome length requires an lncRNA (e.g., hTERC) and two lncRNAs in the ribosome that are required for protein synthesis. Thus, lncRNAs can represent powerful RNA machines. More recently, it has become clear that mammalian genomes encode thousands more lncRNAs. Thus, we raise the question: Which, if any, of these lncRNAs could also represent RNA-based machines? Here we synthesize studies that are beginning to address this question by investigating fundamental properties of lncRNA genes, revealing new insights into the RNA structure-function relationship, determining cis- and trans-acting lncRNAs in vivo, and generating new developments in high-throughput screening used to identify functional lncRNAs. Overall, these findings provide a context toward understanding the molecular grammar underlying lncRNA biology.

几十年来,我们已经知道长链非编码rna (lncrna)可以在大多数生命形式中发挥重要作用。染色体长度的维持需要一个lncRNA(如hTERC)和核糖体中的两个lncRNA,这些lncRNA是蛋白质合成所必需的。因此,lncrna可以代表强大的RNA机器。最近,哺乳动物基因组编码了数千个lncrna已经变得很清楚。因此,我们提出了一个问题:如果有的话,这些lncrna中的哪一个也可以代表基于rna的机器?在这里,我们通过研究lncRNA基因的基本特性,揭示RNA结构-功能关系的新见解,确定体内顺式和反式lncRNA,以及在用于鉴定功能性lncRNA的高通量筛选方面取得新的进展,综合了开始解决这个问题的研究。总的来说,这些发现为理解lncRNA生物学的分子语法提供了一个背景。
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引用次数: 153
Synthetic Genomes. 合成基因组。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-06-20 DOI: 10.1146/annurev-biochem-013118-110704
Weimin Zhang, Leslie A Mitchell, Joel S Bader, Jef D Boeke

DNA synthesis technology has progressed to the point that it is now practical to synthesize entire genomes. Quite a variety of methods have been developed, first to synthesize single genes but ultimately to massively edit or write from scratch entire genomes. Synthetic genomes can essentially be clones of native sequences, but this approach does not teach us much new biology. The ability to endow genomes with novel properties offers special promise for addressing questions not easily approachable with conventional gene-at-a-time methods. These include questions about evolution and about how genomes are fundamentally wired informationally, metabolically, and genetically. The techniques and technologies relating to how to design, build, and deliver big DNA at the genome scale are reviewed here. A fuller understanding of these principles may someday lead to the ability to truly design genomes from scratch.

DNA合成技术已经发展到现在可以合成整个基因组的程度。各种各样的方法已经被开发出来,首先是合成单个基因,但最终是大规模编辑或从头编写整个基因组。合成基因组本质上可以是原生序列的克隆,但这种方法并没有教给我们很多新的生物学知识。赋予基因组新特性的能力为解决传统的一次基因检测方法难以解决的问题提供了特殊的希望。这些问题包括关于进化的问题,以及基因组在信息、代谢和基因方面是如何从根本上连接在一起的问题。本文回顾了与如何在基因组尺度上设计、构建和传递大DNA相关的技术和技术。对这些原理的更全面的理解可能有一天会让我们有能力真正从头开始设计基因组。
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引用次数: 40
Structural and Mechanistic Principles of ABC Transporters. ABC转运体的结构和机械原理。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-06-20 DOI: 10.1146/annurev-biochem-011520-105201
Christoph Thomas, Robert Tampé

ATP-binding cassette (ABC) transporters constitute one of the largest and most ancient protein superfamilies found in all living organisms. They function as molecular machines by coupling ATP binding, hydrolysis, and phosphate release to translocation of diverse substrates across membranes. The substrates range from vitamins, steroids, lipids, and ions to peptides, proteins, polysaccharides, and xenobiotics. ABC transporters undergo substantial conformational changes during substrate translocation. A comprehensive understanding of their inner workings thus requires linking these structural rearrangements to the different functional state transitions. Recent advances in single-particle cryogenic electron microscopy have not only delivered crucial information on the architecture of several medically relevant ABC transporters and their supramolecular assemblies, including the ATP-sensitive potassium channel and the peptide-loading complex, but also made it possible to explore the entire conformational space of these nanomachines under turnover conditions and thereby gain detailed mechanistic insights into their mode of action.

atp结合盒(ABC)转运体构成了所有生物体中发现的最大和最古老的蛋白质超家族之一。它们通过将ATP结合、水解和磷酸盐释放耦合到不同底物跨膜的易位而发挥分子机器的作用。底物范围从维生素、类固醇、脂质和离子到肽、蛋白质、多糖和异种生物。在底物易位过程中,ABC转运蛋白发生了实质性的构象变化。因此,对其内部工作的全面理解需要将这些结构重排与不同的功能状态转换联系起来。单粒子低温电子显微镜的最新进展不仅提供了几种与医学相关的ABC转运体及其超分子组装体(包括atp敏感的钾通道和肽负载复合物)的结构的关键信息,而且还使探索这些纳米机器在周转条件下的整个构象空间成为可能,从而获得详细的机制洞察其作用模式。
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引用次数: 189
Checkpoint Responses to DNA Double-Strand Breaks. DNA双链断裂的检查点反应。
IF 12.1 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-06-20 Epub Date: 2020-03-16 DOI: 10.1146/annurev-biochem-011520-104722
David P Waterman, James E Haber, Marcus B Smolka

Cells confront DNA damage in every cell cycle. Among the most deleterious types of DNA damage are DNA double-strand breaks (DSBs), which can cause cell lethality if unrepaired or cancers if improperly repaired. In response to DNA DSBs, cells activate a complex DNA damage checkpoint (DDC) response that arrests the cell cycle, reprograms gene expression, and mobilizes DNA repair factors to prevent the inheritance of unrepaired and broken chromosomes. Here we examine the DDC, induced by DNA DSBs, in the budding yeast model system and in mammals.

细胞在每个细胞周期中都会面临DNA损伤。最有害的DNA损伤类型是DNA双链断裂(DSBs),如果不修复,可能导致细胞死亡,如果修复不当,可能导致癌症。在DNA dsb的反应中,细胞激活复杂的DNA损伤检查点(DDC)反应,阻止细胞周期,重新编程基因表达,并动员DNA修复因子来防止未修复和断裂染色体的遗传。在这里,我们研究了DNA dsb在出芽酵母模型系统和哺乳动物中诱导的DDC。
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引用次数: 0
Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets. 核糖核苷酸还原酶:核糖核苷酸还原酶:结构、化学和代谢揭示了新的治疗靶点。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-06-20 DOI: 10.1146/annurev-biochem-013118-111843
Brandon L Greene, Gyunghoon Kang, Chang Cui, Marina Bennati, Daniel G Nocera, Catherine L Drennan, JoAnne Stubbe

Ribonucleotide reductases (RNRs) catalyze the de novo conversion of nucleotides to deoxynucleotides in all organisms, controlling their relative ratios and abundance. In doing so, they play an important role in fidelity of DNA replication and repair. RNRs' central role in nucleic acid metabolism has resulted in five therapeutics that inhibit human RNRs. In this review, we discuss the structural, dynamic, and mechanistic aspects of RNR activity and regulation, primarily for the human and Escherichia coli class Ia enzymes. The unusual radical-based organic chemistry of nucleotide reduction, the inorganic chemistry of the essential metallo-cofactor biosynthesis/maintenance, the transport of a radical over a long distance, and the dynamics of subunit interactions all present distinct entry points toward RNR inhibition that are relevant for drug discovery. We describe the current mechanistic understanding of small molecules that target different elements of RNR function, including downstream pathways that lead to cell cytotoxicity. We conclude by summarizing novel and emergent RNR targeting motifs for cancer and antibiotic therapeutics.

核糖核苷酸还原酶(RNRs)在所有生物体内催化核苷酸向脱氧核苷酸的新转化,控制它们的相对比例和丰度。因此,它们在 DNA 复制和修复的保真度方面发挥着重要作用。RNRs 在核酸代谢中的核心作用催生了五种抑制人类 RNRs 的疗法。在这篇综述中,我们将主要针对人类和大肠杆菌 Ia 类酶,讨论 RNR 活性和调控的结构、动态和机理方面。核苷酸还原过程中不寻常的基于自由基的有机化学、重要金属辅助因子的生物合成/维护的无机化学、自由基的长距离运输以及亚基相互作用的动力学都为 RNR 抑制提供了与药物发现相关的独特切入点。我们描述了目前针对 RNR 功能不同要素的小分子的机理认识,包括导致细胞毒性的下游途径。最后,我们总结了用于癌症和抗生素治疗的新型和新兴 RNR 靶向基团。
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引用次数: 0
Detection and Degradation of Stalled Nascent Chains via Ribosome-Associated Quality Control. 通过核糖体相关质量控制检测和降解停滞新生链。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-06-20 DOI: 10.1146/annurev-biochem-013118-110729
Cole S Sitron, Onn Brandman

Stalled protein synthesis produces defective nascent chains that can harm cells. In response, cells degrade these nascent chains via a process called ribosome-associated quality control (RQC). Here, we review the irregularities in the translation process that cause ribosomes to stall as well as how cells use RQC to detect stalled ribosomes, ubiquitylate their tethered nascent chains, and deliver the ubiquitylated nascent chains to the proteasome. We additionally summarize how cells respond to RQC failure.

停滞的蛋白质合成会产生有缺陷的新生链,从而伤害细胞。作为反应,细胞通过一种称为核糖体相关质量控制(RQC)的过程降解这些新生链。在这里,我们回顾了导致核糖体停滞的翻译过程中的不规则性,以及细胞如何使用RQC来检测停滞的核糖体,将其束缚的新生链泛素化,并将泛素化的新生链递送到蛋白酶体。我们还总结了细胞对RQC失效的反应。
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引用次数: 49
HLAs, TCRs, and KIRs, a Triumvirate of Human Cell-Mediated Immunity. hla, tcr和kir,人类细胞介导免疫的三驾马车。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-06-20 DOI: 10.1146/annurev-biochem-011520-102754
Zakia Djaoud, Peter Parham

In all human cells, human leukocyte antigen (HLA) class I glycoproteins assemble with a peptide and take it to the cell surface for surveillance by lymphocytes. These include natural killer (NK) cells and γδ T cells of innate immunity and αβ T cells of adaptive immunity. In healthy cells, the presented peptides derive from human proteins, to which lymphocytes are tolerant. In pathogen-infected cells, HLA class I expression is perturbed. Reduced HLA class I expression is detected by KIR and CD94:NKG2A receptors of NK cells. Almost any change in peptide presentation can be detected by αβ CD8+ T cells. In responding to extracellular pathogens, HLA class II glycoproteins, expressed by specialized antigen-presenting cells, present peptides to αβ CD4+ T cells. In comparison to the families of major histocompatibility complex (MHC) class I, MHC class II and αβ T cell receptors, the antigenic specificity of the γδ T cell receptors is incompletely understood.

在所有人类细胞中,人类白细胞抗原(HLA) I类糖蛋白与肽结合,并将其带到细胞表面供淋巴细胞监视。这些细胞包括天然免疫的NK细胞、γδ T细胞和适应性免疫的αβ T细胞。在健康细胞中,所呈现的肽来源于人蛋白,淋巴细胞对其具有耐受性。在病原体感染的细胞中,HLA I类表达受到干扰。通过NK细胞的KIR和CD94:NKG2A受体检测HLA I类表达降低。αβ CD8+ T细胞几乎可以检测到肽呈现的任何变化。在对细胞外病原体的应答中,HLA II类糖蛋白通过特异性抗原呈递细胞表达,向αβ CD4+ T细胞呈递肽。与主要组织相容性复合体(MHC) I类、MHC II类和αβ T细胞受体家族相比,γδ T细胞受体的抗原特异性尚不完全清楚。
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引用次数: 41
Molecular Mechanisms of Facultative Heterochromatin Formation: An X-Chromosome Perspective. 兼性异染色质形成的分子机制:一个x染色体的视角。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-06-20 Epub Date: 2020-07-07 DOI: 10.1146/annurev-biochem-062917-012655
Jan J Żylicz, Edith Heard

Facultative heterochromatin (fHC) concerns the developmentally regulated heterochromatinization of different regions of the genome and, in the case of the mammalian X chromosome and imprinted loci, of only one allele of a homologous pair. The formation of fHC participates in the timely repression of genes, by resisting strong trans activators. In this review, we discuss the molecular mechanisms underlying the establishment and maintenance of fHC in mammals using a mouse model. We focus on X-chromosome inactivation (XCI) as a paradigm for fHC but also relate it to genomic imprinting and homeobox (Hox) gene cluster repression. A vital role for noncoding transcription and/or transcripts emerges as the general principle of triggering XCI and canonical imprinting. However, other types of fHC are established through an unknown mechanism, independent of noncoding transcription (Hox clusters and noncanonical imprinting). We also extensively discuss polycomb-group repressive complexes (PRCs), which frequently play a vital role in fHC maintenance.

兼性异染色质(fHC)涉及基因组不同区域的发育调节异染色质化,在哺乳动物X染色体和印迹位点的情况下,同源对中只有一个等位基因。fHC的形成通过抵抗强反式激活剂参与了基因的及时抑制。在这篇综述中,我们通过小鼠模型讨论了哺乳动物fHC建立和维持的分子机制。我们将重点放在x染色体失活(XCI)作为fHC的范例,但也将其与基因组印记和同源盒(Hox)基因簇抑制联系起来。非编码转录和/或转录体的重要作用是触发XCI和规范印记的一般原则。然而,其他类型的fHC是通过一种未知的机制建立的,独立于非编码转录(Hox簇和非规范印迹)。我们还广泛讨论了在fHC维持中经常起重要作用的polycomb-group suppression complexes (prc)。
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引用次数: 45
ADP-ribosylation. ADP-ribosylation。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-02-02 DOI: 10.32388/tr7tjc
K. Ueda, O. Hayaishi
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引用次数: 239
Chromatin. 染色质。
IF 16.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2020-02-02 DOI: 10.32388/s9htxi
T. Igo-Kemenes, W. Hörz, H. Zachau
The approximate shape of the chromatin subunit called the nucleosome is now known, but its internal architecture is not well understood. Recent studies reveal details of the organisation of DNA within the nucleosome, and show that the arginine-rich histones are essential to DNA folding. Nucleosomes or structures related to them seem to be present at points of DNA replication and transcription; interactions within and between nucleosomes are likely to play a critical part in these processes.
染色质亚单位核小体的大致形状现在已经知道,但其内部结构尚不清楚。最近的研究揭示了核小体内DNA组织的细节,并表明富含精氨酸的组蛋白对DNA折叠至关重要。核小体或与其相关的结构似乎存在于DNA复制和转录点;核小体内部和核小体之间的相互作用可能在这些过程中发挥关键作用。
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引用次数: 0
期刊
Annual review of biochemistry
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