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A small molecule that reshapes the chromatin dynamics of FOXA1 重塑 FOXA1 染色质动力学的小分子
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-07 DOI: 10.1016/j.molcel.2024.10.019
Khadija Shahed Khan, Billy Wai-Lung Ng
In this issue, Won et al.1 report a covalent ligand binding the pioneer transcription factor FOXA1, altering its function and remodeling chromatin. This important finding highlights the potential of small molecules to modulate transcription factor activity and demonstrates the promise of chemical proteomics in discovering first-in-class ligands.
在本期杂志中,Won 等人1 报告了一种共价配体能与先锋转录因子 FOXA1 结合,改变其功能并重塑染色质。这一重要发现凸显了小分子调节转录因子活性的潜力,并证明了化学蛋白质组学在发现一流配体方面的前景。
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引用次数: 0
Inducing rice chilling tolerance by the second messenger 2′,3′-cAMP 第二信使 2′,3′-cAMP 诱导水稻耐寒性
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-07 DOI: 10.1016/j.molcel.2024.10.013
Zhifu Han, Yu Cao, Jijie Chai
In this issue of Molecular Cell, Luo et al.1 identify a signaling pathway, OSM1-COLD6, that induces cold tolerance in rice by promoting production of the non-canonical cyclic nucleotide 2′,3′-cAMP. The study opens new avenues for enhancing cold tolerance in rice breeding.
在本期《分子细胞》(Molecular Cell)杂志上,Luo 等人1 发现了一种信号通路 OSM1-COLD6,它通过促进非经典环状核苷酸 2′,3′-cAMP 的产生来诱导水稻的耐寒性。这项研究为提高水稻育种的耐寒性开辟了新途径。
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引用次数: 0
Cap-specific m6Am modification: A transcriptional anti-terminator by sequestering PCF11 with implications for neuroblastoma therapy 帽子特异性 m6Am 修饰:通过封存 PCF11 成为转录反终止子,对神经母细胞瘤治疗具有重要意义
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-07 DOI: 10.1016/j.molcel.2024.10.014
Shinichiro Akichika, Tsutomu Suzuki
In this issue of Molecular Cell, An et al.1 reports a novel function of cap-specific m6Am modification acting as an anti-terminator for premature RNA polymerase II transcription by sequestering a transcriptional terminator PCF11. This study provides new insights into RNA modifications in transcriptional control and cancer treatment.
在本期的《分子细胞》(Molecular Cell)杂志上,An 等人1 报道了帽特异性 m6Am 修饰的一种新功能,即通过封存转录终止子 PCF11 来作为 RNA 聚合酶 II 过早转录的抗终止子。这项研究为转录控制和癌症治疗中的 RNA 修饰提供了新的见解。
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引用次数: 0
A road to rupture: New insights into the loss of micronuclear membrane integrity 通向破裂之路:对微核膜完整性丧失的新认识
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-07 DOI: 10.1016/j.molcel.2024.10.018
Shane M. Harding
In two recent studies in Science, Martin et al. and Di Bona et al.1,2 showed that mitochondrial-derived reactive oxygen species (ROS) drive mechanisms responsible for micronuclei membrane rupture, with important implications for cancer.
马丁等人和迪博纳等人最近在《科学》杂志上发表的两项研究1,2 表明,线粒体产生的活性氧(ROS)驱动了微核膜破裂的机制,对癌症具有重要影响。
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引用次数: 0
A functional connection between the Microprocessor and a variant NEXT complex 微处理器与变体 NEXT 复合物之间的功能连接
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-07 DOI: 10.1016/j.molcel.2024.10.015
Katsutoshi Imamura, William Garland, Manfred Schmid, Lis Jakobsen, Kengo Sato, Jérôme O. Rouvière, Kristoffer Pors Jakobsen, Elena Burlacu, Marta Loureiro Lopez, Søren Lykke-Andersen, Jens S. Andersen, Torben Heick Jensen
In mammalian cells, primary miRNAs are cleaved at their hairpin structures by the Microprocessor complex, whose core is composed of DROSHA and DGCR8. Here, we show that 5′ flanking regions, resulting from Microprocessor cleavage, are targeted by the RNA exosome in mouse embryonic stem cells (mESCs). This is facilitated by a physical link between DGCR8 and the nuclear exosome targeting (NEXT) component ZCCHC8. Surprisingly, however, both biochemical and mutagenesis studies demonstrate that a variant NEXT complex, containing the RNA helicase MTR4 but devoid of the RNA-binding protein RBM7, is the active entity. This Microprocessor-NEXT variant also targets stem-loop-containing RNAs expressed from other genomic regions, such as enhancers. By contrast, Microprocessor does not contribute to the turnover of less structured NEXT substrates. Our results therefore demonstrate that MTR4-ZCCHC8 can link to either RBM7 or DGCR8/DROSHA to target different RNA substrates depending on their structural context.
在哺乳动物细胞中,初级miRNA在其发夹结构处被Microprocessor复合体裂解,该复合体的核心由DROSHA和DGCR8组成。在这里,我们发现,在小鼠胚胎干细胞(mESCs)中,由微处理器裂解产生的5′侧翼区域是RNA外泌体的靶标。DGCR8与核外泌体靶向(NEXT)元件ZCCHC8之间的物理联系促进了这一过程。然而,令人惊讶的是,生化研究和诱变研究都表明,含有 RNA 螺旋酶 MTR4 但没有 RNA 结合蛋白 RBM7 的变体 NEXT 复合物才是活跃的实体。这种微处理器-NEXT变体也以其他基因组区域(如增强子)表达的含茎环 RNA 为靶标。相比之下,Microprocessor 不参与结构较少的 NEXT 底物的周转。因此,我们的研究结果表明,MTR4-ZCCHC8 可以与 RBM7 或 DGCR8/DROSHA 连接,根据不同的结构背景靶向不同的 RNA 底物。
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引用次数: 0
Structures and pH-dependent dimerization of the sevenless receptor tyrosine kinase 无七受体酪氨酸激酶的结构和 pH 依赖性二聚化
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-06 DOI: 10.1016/j.molcel.2024.10.017
Gabriele Cerutti, Ronald Arias, Fabiana Bahna, Seetha Mannepalli, Phinikoula S. Katsamba, Goran Ahlsen, Brian Kloss, Renato Bruni, Andrew Tomlinson, Lawrence Shapiro
Sevenless (Sev) is a Drosophila receptor tyrosine kinase (RTK) required for the specification of the R7 photoreceptor. It is cleaved into α and β subunits and binds the ectodomain of the G-protein-coupled receptor bride of sevenless (Boss). Previous work showed that the Boss ectodomain could bind but not activate Sev; rather, the whole seven-pass transmembrane Boss was required. Here, we show that Sev does not need to be cleaved to function and that a single-pass transmembrane form of Boss activates Sev. We use cryo-electron microscopy and biophysical methods to determine the structural basis of ligand binding and pH-dependent dimerization of Sev, and we discuss the implications in the process of Sev activation. The Sev human homolog, receptor oncogene from sarcoma 1 (ROS1), is associated with oncogenic transformations, and we discuss their structural similarities.
七无(Sev)是果蝇受体酪氨酸激酶(RTK),R7感光器的规格化需要它。它被裂解成 α 和 β 亚基,并与七无 G 蛋白偶联受体新娘(Boss)的外显子结合。以前的研究表明,Boss 外结构域能与 Sev 结合,但不能激活 Sev;相反,需要整个七孔跨膜 Boss。在这里,我们证明 Sev 不需要被裂解就能发挥作用,而且单通跨膜形式的 Boss 能激活 Sev。我们使用冷冻电镜和生物物理方法确定了配体结合和 Sev 的 pH 依赖性二聚化的结构基础,并讨论了 Sev 激活过程中的影响。Sev 的人类同源物肉瘤受体癌基因 1(ROS1)与致癌转化有关,我们讨论了它们在结构上的相似性。
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引用次数: 0
Profound synthetic lethality between SMARCAL1 and FANCM SMARCAL1 和 FANCM 之间的合成致死率很高
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-06 DOI: 10.1016/j.molcel.2024.10.016
Sumin Feng, Kaiwen Liu, Jinfeng Shang, Lisa Hoeg, Graziana Pastore, William Yang, Sabrina Roy, Guillermo Sastre-Moreno, Jordan T.F. Young, Wei Wu, Dongyi Xu, Daniel Durocher
DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens in human cells with three SNF2-type ATPases: SMARCAL1, ZRANB3, and HLTF. Here, we show that SMARCAL1 displays a profound synthetic-lethal interaction with FANCM, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.
DNA 复制压力是对基因组完整性的一种威胁。大型 SNF2 ATP 酶家族利用 ATP 驱动的马达重塑 DNA 或 DNA 结合蛋白,从而参与预防和减轻 DNA 复制压力。为了了解这些 ATP 酶在基因组维护中的贡献,我们在人体细胞中利用三种 SNF2 型 ATP 酶进行了基于 CRISPR 的合成致死筛选:SMARCAL1、ZRANB3 和 HLTF。在这里,我们发现 SMARCAL1 与 FANCM(另一种参与 DNA 复制和基因组稳定性的 ATP 依赖性转运酶)之间存在深远的合成致死相互作用。它们的共同缺失会导致严重的基因组不稳定性,我们将这种不稳定性与染色体在富含简单重复序列的位点上的断裂联系起来,众所周知,简单重复序列会挑战复制叉的进展。我们的发现揭示了一种关键的遗传缓冲机制,它为维持基因组完整性提供了重要功能。
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引用次数: 0
Redundant pathways for removal of defective RNA polymerase II complexes at a promoter-proximal pause checkpoint 在启动子近端暂停检查点清除有缺陷的 RNA 聚合酶 II 复合物的冗余途径
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-05 DOI: 10.1016/j.molcel.2024.10.012
Daniel Blears, Jiangman Lou, Nova Fong, Richard Mitter, Ryan M. Sheridan, Dandan He, A. Barbara Dirac-Svejstrup, David Bentley, Jesper Q. Svejstrup
The biological purpose of Integrator and RNA polymerase II (RNAPII) promoter-proximal pausing remains uncertain. Here, we show that loss of INTS6 in human cells results in increased interaction of RNAPII with proteins that can mediate its dissociation from the DNA template, including the CRL3ARMC5 E3 ligase, which ubiquitylates CTD serine5-phosphorylated RPB1 for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors acting at the promoter-proximal pause, including Integrator, DSIF, and capping enzyme. This ARMC5 checkpoint normally curtails a sizeable fraction of RNAPII transcription, and ARMC5 knockout cells produce more uncapped transcripts. When both the Integrator and CRL3ARMC5 turnover mechanisms are compromised, cell growth ceases and RNAPII with high pausing propensity disperses from the promoter-proximal pause site into the gene body. These data support a model in which CRL3ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.
整合子和 RNA 聚合酶 II(RNAPII)启动子近端暂停的生物学目的仍不确定。在这里,我们发现人类细胞中 INTS6 的缺失导致 RNAPII 与能介导其从 DNA 模板解离的蛋白质的相互作用增加,其中包括 CRL3ARMC5 E3 连接酶,它能泛素化 CTD 丝氨酸 5 磷酸化的 RPB1,使其降解。ARMC5 依赖性 RNAPII 泛素化是由作用于启动子近端暂停的因子(包括整合因子、DSIF 和封顶酶)的缺陷激活的。ARMC5 检查点通常会抑制相当一部分的 RNAPII 转录,而 ARMC5 基因敲除细胞会产生更多的未封顶转录本。当整合子和 CRL3ARMC5 的转换机制都受到破坏时,细胞生长停止,具有高暂停倾向的 RNAPII 从启动子近端暂停位点分散到基因体中。这些数据支持一种模型,即 CRL3ARMC5 与 Integrator 一起在检查点机制中发挥作用,清除启动子近端暂停位点上有问题的 RNAPII 复合物,以保护转录完整性。
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引用次数: 0
Threonine-rich carboxyl-terminal extension drives aggregation of stalled polypeptides 富含苏氨酸的羧基末端延伸推动了停滞多肽的聚集
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 DOI: 10.1016/j.molcel.2024.10.011
Weili Denyse Chang, Mi-Jeong Yoon, Kian Hua Yeo, Young-Jun Choe
Ribosomes translating damaged mRNAs may stall and prematurely split into their large and small subunits. The split large ribosome subunits can continue elongating stalled polypeptides. In yeast, this mRNA-independent translation appends the C-terminal alanine/threonine tail (CAT tail) to stalled polypeptides. If not degraded by the ribosome-associated quality control (RQC), CAT-tailed stalled polypeptides form aggregates. How the CAT tail, a low-complexity region composed of alanine and threonine, drives protein aggregation remains unknown. In this study, we demonstrate that C-terminal polythreonine or threonine-enriched tails form detergent-resistant aggregates. These aggregates exhibit a robust seeding effect on shorter tails with lower threonine content, elucidating how heterogeneous CAT tails co-aggregate. Polythreonine aggregates sequester molecular chaperones, disturbing proteostasis and provoking the heat shock response. Furthermore, polythreonine cross-seeds detergent-resistant polyserine aggregation, indicating structural similarity between the two aggregates. This study identifies polythreonine and polyserine as a distinct group of aggregation-prone protein motifs.
翻译受损 mRNA 的核糖体可能会停滞,并过早地分裂成大亚基和小亚基。分裂后的大核糖体亚基可以继续延长停滞的多肽。在酵母中,这种不依赖于 mRNA 的翻译会将 C 端丙氨酸/苏氨酸尾(CAT 尾)附加到停滞的多肽上。如果不被核糖体相关质量控制(RQC)降解,CAT 尾的滞留多肽就会形成聚集体。CAT 尾部是一个由丙氨酸和苏氨酸组成的低复杂性区域,它是如何驱动蛋白质聚集的仍是未知数。在这项研究中,我们证明了 C 端富含多苏氨酸或苏氨酸的尾部会形成抗清洁剂的聚集体。这些聚集体对苏氨酸含量较低的较短尾部表现出强大的播种效应,从而阐明了异质 CAT 尾部是如何共同聚集的。多苏氨酸聚集体会封闭分子伴侣,扰乱蛋白稳态并引发热休克反应。此外,聚苏氨酸还能交叉融合抗清洁剂的聚丝氨酸聚集体,这表明这两种聚集体在结构上具有相似性。这项研究确定了聚苏氨酸和聚丝氨酸是一组不同的易聚集蛋白质基团。
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引用次数: 0
Spatial organization of PI3K-PI(3,4,5)P3-AKT signaling by focal adhesions 病灶粘连对 PI3K-PI(3,4,5)P3-AKT 信号传导的空间组织作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-01 DOI: 10.1016/j.molcel.2024.10.010
Jing Wang, Zhengyang An, Zhongsheng Wu, Wei Zhou, Pengyu Sun, Piyu Wu, Song Dang, Rui Xue, Xue Bai, Yongtao Du, Rongmei Chen, Wenxu Wang, Pei Huang, Sin Man Lam, Youwei Ai, Suling Liu, Guanghou Shui, Zhe Zhang, Zheng Liu, Jianyong Huang, Kangmin He
The class I phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is a key regulator of cell survival, growth, and proliferation and is among the most frequently mutated pathways in cancer. However, where and how PI3K-AKT signaling is spatially activated and organized in mammalian cells remains poorly understood. Here, we identify focal adhesions (FAs) as subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P3-AKT signaling in human cancer cells containing p110α mutations under basal conditions. We find that class IA PI3Ks are preferentially recruited to FAs for activation, resulting in localized production of PI(3,4,5)P3 around FAs. As the effector protein of PI(3,4,5)P3, AKT1 molecules are dynamically recruited around FAs for activation. The spatial recruitment/activation of the PI3K-PI(3,4,5)P3-AKT cascade is regulated by activated FA kinase (FAK). Furthermore, combined inhibition of p110α and FAK results in a more potent inhibitory effect on cancer cells. Thus, our results unveil a growth-factor independent, compartmentalized organization mechanism for PI3K-PI(3,4,5)P3-AKT signaling.
I 类磷脂酰肌醇 3- 激酶(PI3K)-AKT 信号通路是细胞存活、生长和增殖的关键调节因子,也是癌症中最常发生突变的通路之一。然而,人们对哺乳动物细胞中 PI3K-AKT 信号在何处以及如何在空间上被激活和组织仍然知之甚少。在这里,我们发现在含有 p110α 突变的人类癌细胞中,病灶粘附(FA)是亚细胞信号中枢,在基础条件下组织激活 PI3K-PI(3,4,5)P3-AKT 信号。我们发现,IA类PI3K优先被招募到FAs上进行激活,从而在FAs周围局部产生PI(3,4,5)P3。作为 PI(3,4,5)P3 的效应蛋白,AKT1 分子被动态地招募到 FAs 周围进行激活。PI3K-PI(3,4,5)P3-AKT 级联的空间招募/激活受活化的 FA 激酶(FAK)调控。此外,联合抑制 p110α 和 FAK 能对癌细胞产生更强的抑制作用。因此,我们的研究结果揭示了独立于生长因子的 PI3K-PI(3,4,5)P3-AKT 信号传导的分区组织机制。
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引用次数: 0
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Molecular Cell
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