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Rethinking transcription factor dynamics and transcription regulation in eukaryotes.
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-04 DOI: 10.1016/j.tibs.2025.01.012
Reiner A Veitia

Transcription factors (TFs) control gene expression by binding to specific DNA motifs in cis-regulatory elements. Cooperativity has been thought to ensure TF binding specificity. Recent research suggests that, at least in yeast, the role of cooperativity has probably been overemphasized. Consequently, synergy - the collective recruitment of the transcriptional machinery by TFs bound at multiple DNA sites - emerges as a more significant mechanism for achieving the specificity of the transcriptional response. Furthermore, I argue that the concentration of TFs within phase-separated nuclear condensates and their covalent modifications play an underappreciated but crucial role in sharpening transcriptional responses through complementary mechanisms. A model integrating cooperativity, synergy, post-translational modifications, and phase separation provides a comprehensive framework to explain dynamic, context-specific transcriptional responses in eukaryotes.

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引用次数: 0
Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/j.tibs.2024.12.010
John D. Hayes , Sharadha Dayalan Naidu , Albena T. Dinkova-Kostova
Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates defenses against oxidants and thiol-reactive electrophiles. It is controlled at the protein stability level by several E3 ubiquitin ligases (CRL3Keap1, CRL4DCAF11, SCFβ-TrCP, and Hrd1). CRL3Keap1 is of the greatest importance because it constitutively targets Nrf2 for proteasomal degradation under homeostatic conditions but is prevented from doing so by oxidative stressors. Repression of Nrf2 by CRL3Keap1 is attenuated by SQSTM1/p62, and this is reinforced by phosphorylation of SQSTM1/p62. Repression by SCFβ-TrCP requires phosphorylation of Nrf2 by GSK3, the activity of which is inhibited by PKB/Akt and other kinases. We discuss how Nrf2 activity is controlled by the ubiquitin ligases under different circumstances. We also describe endogenous signaling molecules that inactivate CRL3Keap1 to alleviate stress and restore homeostasis.
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引用次数: 0
Stress responses induced by perturbation of the ubiquitin–proteasome system 泛素-蛋白酶体系统扰动诱导的应激反应。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/j.tibs.2024.12.011
Mamta Rai , Liam C. Hunt , Fabio Demontis
The ubiquitin–proteasome system is key for proteostasis and its disruption can induce several cellular adaptations. Here, we summarize the range of cellular responses that are induced by perturbation of distinct components of the ubiquitin–proteasome system, and how proteasome stress in a tissue can induce systemic responses in distant tissues.
泛素-蛋白酶体系统是蛋白质平衡的关键，它的破坏可以诱导几种细胞适应。在这里，我们总结了泛素-蛋白酶体系统的不同组成部分的扰动所诱导的细胞反应的范围，以及组织中的蛋白酶体应激如何在远处组织中诱导全身反应。
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引用次数: 0
Journey to the past: molecular de-extinction enables the discovery of ancient β-defensins and highlights their evolutionary history 过去的旅程：分子去灭绝使发现古代β-防御素和突出他们的进化史。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/j.tibs.2024.12.002
Françoise Gosti
Molecular de-extinction is an innovative science aiming to discover, synthesize, and characterize molecules throughout evolution. Recent work by Ferreira et al. involved mining ancient genomes to search for antimicrobial defensins. They discovered six ancient β-defensins, revealing their evolutionary history and uncovering their structural and biochemical properties, which could feed medical applications.
分子去灭绝是一门创新的科学，旨在发现、合成和表征整个进化过程中的分子。Ferreira等人最近的工作涉及挖掘古代基因组以寻找抗微生物防御素。他们发现了六种古老的β-防御素，揭示了它们的进化历史，揭示了它们的结构和生化特性，这可以为医学应用提供依据。
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引用次数: 0
Mechanisms and rationales of SAM homeostasis SAM稳态的机制和原理。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/j.tibs.2024.12.009
Zheng Xing , Benjamin P. Tu
S-Adenosylmethionine (SAM) is the primary methyl donor for numerous cellular methylation reactions. Its central role in methylation and involvement with many pathways link its availability to the regulation of cellular processes, the dysregulation of which can contribute to disease states, such as cancer or neurodegeneration. Emerging evidence indicates that intracellular SAM levels are maintained within an optimal range by a variety of homeostatic mechanisms. This suggests that the need to maintain SAM homeostasis represents a significant evolutionary pressure across all kingdoms of life. Here, we review how SAM controls cellular functions at the molecular level and discuss strategies to maintain SAM homeostasis. We propose that SAM exerts a broad and underappreciated influence in cellular regulation that remains to be fully elucidated.
s -腺苷蛋氨酸（SAM）是许多细胞甲基化反应的主要甲基供体。它在甲基化中的核心作用和参与许多途径将其与细胞过程的调节联系起来，细胞过程的失调可能导致疾病状态，如癌症或神经退行性变。新出现的证据表明，细胞内SAM水平通过各种稳态机制维持在最佳范围内。这表明，维持SAM稳态的需要代表了所有生命领域的重大进化压力。在这里，我们回顾了SAM如何在分子水平上控制细胞功能，并讨论了维持SAM稳态的策略。我们认为，SAM在细胞调控中发挥了广泛而未被充分认识的影响，这一影响仍有待充分阐明。
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引用次数: 0
Glucokinase: from allosteric glucose sensing to disease variants 葡萄糖激酶：从变构葡萄糖感应到疾病变异。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/j.tibs.2024.12.007
Sarah Gersing , Torben Hansen , Kresten Lindorff-Larsen , Rasmus Hartmann-Petersen
Human glucokinase (GCK) functions as a glucose sensor in the pancreas and liver, where GCK activity regulates insulin secretion and glycogen synthesis, respectively. GCK’s low affinity for glucose and the sigmoidal substrate dependency of enzymatic turnover enables it to act as a sensor that makes cells responsive to changes in circulating glucose levels. Its unusual kinetic properties are intrinsically linked to the enzyme’s conformational dynamics. Accordingly, genetic variants that alter the dynamics or other aspects of GCK function are linked to three glucose homeostasis diseases. In this review, we describe the enzyme GCK, focusing on its role as a glucose sensor, its unusual kinetic properties, and recent large-scale efforts to assess GCK variant effects.
人葡萄糖激酶（GCK）在胰腺和肝脏中起葡萄糖传感器的作用，其活性分别调节胰岛素分泌和糖原合成。GCK对葡萄糖的低亲和力和酶周转的s型底物依赖性使其能够作为一种传感器，使细胞对循环葡萄糖水平的变化做出反应。其不同寻常的动力学性质与酶的构象动力学有着内在的联系。因此，改变GCK功能动力学或其他方面的遗传变异与三种葡萄糖稳态疾病有关。在这篇综述中，我们描述了GCK酶，重点是它作为葡萄糖传感器的作用，它不同寻常的动力学性质，以及最近大规模评估GCK变异效应的努力。
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引用次数: 0
Z-DNA at the crossroads: untangling its role in genome dynamics
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/j.tibs.2025.01.001
Vinodh J. Sahayasheela , Mitsuharu Ooga , Tomotaka Kumagai , Hiroshi Sugiyama
DNA can fold into noncanonical left-handed Z-DNA conformation beyond the right-handed B-DNA. While its crystal structure was discovered nearly four decades ago, it was predominantly considered a structural curiosity. Recent evidence suggests that Z-DNA formation occurs in nuclear and mitochondrial DNA (mtDNA), with significant biological implications. However, our understanding of its roles remains in its infancy, primarily due to a lack of study tools. In this review we summarize the structure and function of Z-DNA within the genome while addressing the difficulties associated with identifying and investigating its role(s). We then critically evaluate several intracellular factors that can modulate and regulate Z-DNA. Additionally, we discuss the recent technological and methodological advances that may overcome the challenges and enhance our understanding of Z-DNA.
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引用次数: 0
PARPs and ADP-ribosylation-mediated biomolecular condensates: determinants, dynamics, and disease implications
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/j.tibs.2024.12.013
Hongrui Liu , Meenakshi Pillai , Anthony K.L. Leung
Biomolecular condensates are cellular compartments that selectively enrich proteins and other macromolecules despite lacking enveloping membranes. These compartments often form through phase separation triggered by multivalent nucleic acids. Emerging data have revealed that poly(ADP-ribose) (PAR), a nucleic acid-based protein modification catalyzed by ADP-ribosyltransferases (commonly known as PARPs), plays a crucial role in this process. This review focuses on the role of PARPs and ADP-ribosylation, and explores the principles and mechanisms by which PAR regulates condensate formation, dissolution, and dynamics. Future studies with advanced tools to examine PAR binding sites, substrate interactions, PAR length and structure, and transitions from condensates to aggregates will be key to unraveling the complexity of ADP-ribosylation in health and disease, including cancer, viral infection, and neurodegeneration.
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引用次数: 0
Advisory Board and Contents
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/S0968-0004(25)00035-0
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引用次数: 0
Structured protein domains enter the spotlight: modulators of biomolecular condensate form and function 结构蛋白域进入聚光灯下：生物分子凝聚形式和功能的调节剂。
IF 11.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Trends in Biochemical Sciences
Pub Date : 2025-03-01 DOI: 10.1016/j.tibs.2024.12.008
Nathaniel Hess , Jerelle A. Joseph
Biomolecular condensates are membraneless organelles that concentrate proteins and nucleic acids. One of the primary components of condensates is multidomain proteins, whose domains can be broadly classified as structured and disordered. While structured protein domains are ubiquitous within biomolecular condensates, the physical ramifications of their unique properties have been relatively underexplored. Therefore, this review synthesizes current literature pertaining to structured protein domains within the context of condensates. We examine how the propensity of structured domains for high interaction specificity and low conformational heterogeneity contributes to the formation, material properties, and functions of biomolecular condensates. Finally, we propose unanswered questions on the behavior of structured protein domains within condensates, the answers of which will contribute to a more complete understanding of condensate biophysics.
生物分子凝聚物是浓缩蛋白质和核酸的无膜细胞器。缩聚物的主要组成部分之一是多结构域蛋白，其结构域大致可分为结构化和无序两类。虽然结构蛋白结构域在生物分子凝聚物中无处不在，但其独特性质的物理后果尚未得到相对充分的探索。因此，本文综述了目前有关缩合物结构蛋白结构域的文献。我们研究了高相互作用特异性和低构象异质性的结构域的倾向如何有助于生物分子凝聚物的形成、材料特性和功能。最后，我们提出了关于凝析物中结构蛋白结构域行为的未解问题，这些问题的答案将有助于更全面地理解凝析物的生物物理学。
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引用次数: 0
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