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A FACT about macroH2A removal in immune gene activation 关于免疫基因激活过程中去除宏 H2A 的事实
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.molcel.2024.07.028
Oliver Meers, Marcus Buschbeck

Histone variants contribute to epigenetic regulation in development and disease but require the chaperone machinery for correct deposition. In this issue of Molecular Cell, Ji et al.1 explain how the chaperone complex FACT removes the histone variant macroH2A1.2 and demonstrate its importance for gene activation in innate immune cells.

组蛋白变体有助于发育和疾病过程中的表观遗传调控,但需要伴侣机制才能正确沉积。在本期《分子细胞》(Molecular Cell)杂志上,Ji 等人1 解释了伴侣复合体 FACT 如何去除组蛋白变体 macroH2A1.2,并证明了它对先天性免疫细胞基因激活的重要性。
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引用次数: 0
Ubiquitin gets sweet: Sugar-mediated ubiquitination regulates Nrf1 function 泛素变甜了糖介导的泛素化调节 Nrf1 的功能
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.molcel.2024.07.023
Alison C. Mody, Christina M. Woo

In this issue of Molecular Cell, Yoshida et al.1 report an unconventional sugar-dependent ubiquitination event on Nrf1 that disrupts Nrf1 transcriptional activation.

在本期的《分子细胞》(Molecular Cell)杂志上,Yoshida 等人1 报告了 Nrf1 上的一种非常规糖依赖泛素化事件,该事件破坏了 Nrf1 的转录激活。
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引用次数: 0
RAD51 protects abasic sites to prevent replication fork breakage RAD51 保护消融位点,防止复制叉断裂
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.molcel.2024.07.004
Yodhara Wijesekara Hanthi, Miguel Angel Ramirez-Otero, Robert Appleby, Anna De Antoni, Luay Joudeh, Vincenzo Sannino, Salli Waked, Alessandra Ardizzoia, Viviana Barra, Daniele Fachinetti, Luca Pellegrini, Vincenzo Costanzo

Abasic sites are DNA lesions repaired by base excision repair. Cleavage of unrepaired abasic sites in single-stranded DNA (ssDNA) can lead to chromosomal breakage during DNA replication. How rupture of abasic DNA is prevented remains poorly understood. Here, using cryoelectron microscopy (cryo-EM), Xenopus laevis egg extracts, and human cells, we show that RAD51 nucleofilaments specifically recognize and protect abasic sites, which increase RAD51 association rate to DNA. In the absence of BRCA2 or RAD51, abasic sites accumulate as a result of DNA base methylation, oxidation, and deamination, inducing abasic ssDNA gaps that make replicating DNA fibers sensitive to APE1. RAD51 assembled on abasic DNA prevents abasic site cleavage by the MRE11-RAD50 complex, suppressing replication fork breakage triggered by an excess of abasic sites or POLθ polymerase inhibition. Our study highlights the critical role of BRCA2 and RAD51 in safeguarding against unrepaired abasic sites in DNA templates stemming from base alterations, ensuring genomic stability.

消减位点是通过碱基切除修复的 DNA 损伤。在 DNA 复制过程中,单链 DNA(ssDNA)中未修复的缺损位点的裂解可导致染色体断裂。人们对如何防止缺失 DNA 断裂仍然知之甚少。在这里,我们利用低温电子显微镜(cryo-EM)、爪蟾卵提取物和人类细胞,证明了 RAD51 核丝可特异性识别和保护缺失位点,从而提高 RAD51 与 DNA 的结合率。在缺乏 BRCA2 或 RAD51 的情况下,DNA 碱基甲基化、氧化和脱氨基作用会导致缺失位点积累,从而诱发缺失 ssDNA 间隙,使复制 DNA 纤维对 APE1 敏感。组装在缺损 DNA 上的 RAD51 可阻止 MRE11-RAD50 复合物对缺损位点的裂解,从而抑制因缺损位点过多或 POLθ 聚合酶抑制而引发的复制叉断裂。我们的研究强调了 BRCA2 和 RAD51 在防止 DNA 模板中因碱基改变而产生的未修复的缺损位点、确保基因组稳定性方面的关键作用。
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引用次数: 0
Proteasome resides in and dismantles plant heat stress granules constitutively 蛋白酶体连续驻留在植物热胁迫颗粒中并将其分解
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.molcel.2024.07.033
Zhouli Xie, Shuai Zhao, Yuchen Tu, Enhui Liu, Ying Li, Xingwei Wang, Changtian Chen, Shuwei Zhai, Jie Qi, Chengyun Wu, Honghong Wu, Mian Zhou, Wei Wang

Stress granules (SGs) are conserved reversible cytoplasmic condensates enriched with aggregation-prone proteins assembled in response to various stresses. How plants regulate SG dynamics is unclear. Here, we show that 26S proteasome is a stable component of SGs, promoting the overall clearance of SGs without affecting the molecular mobility of SG components. Increase in either temperature or duration of heat stress reduces the molecular mobility of SG marker proteins and suppresses SG clearance. Heat stress induces dramatic ubiquitylation of SG components and enhances the activities of SG-resident proteasomes, allowing the degradation of SG components even during the assembly phase. Their proteolytic activities enable the timely disassembly of SGs and secure the survival of plant cells during the recovery from heat stress. Therefore, our findings identify the cellular process that de-couples macroscopic dynamics of SGs from the molecular dynamics of its constituents and highlights the significance of the proteasomes in SG disassembly.

应激颗粒(SG)是一种保守的可逆细胞质凝聚体,富含容易聚集的蛋白质,是对各种应激的反应。植物如何调节 SG 的动态尚不清楚。在这里,我们发现 26S 蛋白酶体是 SG 的稳定成分,它能在不影响 SG 成分分子流动性的情况下促进 SG 的整体清除。温度或热胁迫持续时间的增加会降低SG标记蛋白的分子流动性,抑制SG的清除。热应激会诱导 SG 成分发生剧烈的泛素化,并增强 SG 驻留蛋白酶体的活性,使 SG 成分即使在组装阶段也能被降解。蛋白酶体的蛋白水解活性使 SG 得以及时解体,并确保植物细胞在热胁迫恢复期间的存活。因此,我们的研究结果确定了使 SG 的宏观动态与其组成成分的分子动态脱钩的细胞过程,并强调了蛋白酶体在 SG 分解过程中的重要作用。
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引用次数: 0
RNA interacts with topoisomerase I to adjust DNA topology RNA 与拓扑异构酶 I 相互作用,调整 DNA 拓扑结构
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.molcel.2024.07.032
Mannan Bhola, Kouki Abe, Paola Orozco, Homa Rahnamoun, Pedro Avila-Lopez, Elijah Taylor, Nefertiti Muhammad, Bei Liu, Prachi Patel, John F. Marko, Anne C. Starner, Chuan He, Eric L. Van Nostrand, Alfonso Mondragón, Shannon M. Lauberth

Topoisomerase I (TOP1) is an essential enzyme that relaxes DNA to prevent and dissipate torsional stress during transcription. However, the mechanisms underlying the regulation of TOP1 activity remain elusive. Using enhanced cross-linking and immunoprecipitation (eCLIP) and ultraviolet-cross-linked RNA immunoprecipitation followed by total RNA sequencing (UV-RIP-seq) in human colon cancer cells along with RNA electrophoretic mobility shift assays (EMSAs), biolayer interferometry (BLI), and in vitro RNA-binding assays, we identify TOP1 as an RNA-binding protein (RBP). We show that TOP1 directly binds RNA in vitro and in cells and that most RNAs bound by TOP1 are mRNAs. Using a TOP1 RNA-binding mutant and topoisomerase cleavage complex sequencing (TOP1cc-seq) to map TOP1 catalytic activity, we reveal that RNA opposes TOP1 activity as RNA polymerase II (RNAPII) commences transcription of active genes. We further demonstrate the inhibitory role of RNA in regulating TOP1 activity by employing DNA supercoiling assays and magnetic tweezers. These findings provide insight into the coordinated actions of RNA and TOP1 in regulating DNA topological stress intrinsic to RNAPII-dependent transcription.

拓扑异构酶 I(TOP1)是一种重要的酶,它能松弛 DNA 以防止和消除转录过程中的扭转应力。然而,TOP1 活性的调控机制仍然难以捉摸。通过在人结肠癌细胞中使用增强交联免疫沉淀(eCLIP)和紫外线交联 RNA 免疫沉淀,然后进行总 RNA 测序(UV-RIP-seq),以及 RNA 电泳迁移试验(EMSAs)、生物层干涉测量法(BLI)和体外 RNA 结合试验,我们发现 TOP1 是一种 RNA 结合蛋白(RBP)。我们的研究表明,TOP1 在体外和细胞内直接与 RNA 结合,而且与 TOP1 结合的大多数 RNA 都是 mRNA。利用 TOP1 RNA 结合突变体和拓扑异构酶裂解复合物测序(TOP1cc-seq)来绘制 TOP1 催化活性图,我们发现当 RNA 聚合酶 II(RNAPII)开始转录活性基因时,RNA 会对抗 TOP1 的活性。我们利用 DNA 超卷曲测定和磁镊进一步证明了 RNA 在调节 TOP1 活性中的抑制作用。这些发现让我们深入了解了 RNA 和 TOP1 在调节 RNAPII 依赖性转录所固有的 DNA 拓扑应力方面的协调作用。
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引用次数: 0
Role of a holo-insertase complex in the biogenesis of biophysically diverse ER membrane proteins 整体插入酶复合物在生物物理多样性ER膜蛋白的生物生成过程中的作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.molcel.2024.08.005
Katharine R. Page, Vy N. Nguyen, Tino Pleiner, Giovani Pinton Tomaleri, Maxine L. Wang, Alina Guna, Masami Hazu, Ting-Yu Wang, Tsui-Fen Chou, Rebecca M. Voorhees

Mammalian membrane proteins perform essential physiologic functions that rely on their accurate insertion and folding at the endoplasmic reticulum (ER). Using forward and arrayed genetic screens, we systematically studied the biogenesis of a panel of membrane proteins, including several G-protein-coupled receptors (GPCRs). We observed a central role for the insertase, the ER membrane protein complex (EMC), and developed a dual-guide approach to identify genetic modifiers of the EMC. We found that the back of Sec61 (BOS) complex, a component of the multipass translocon, was a physical and genetic interactor of the EMC. Functional and structural analysis of the EMC⋅BOS holocomplex showed that characteristics of a GPCR’s soluble domain determine its biogenesis pathway. In contrast to prevailing models, no single insertase handles all substrates. We instead propose a unifying model for coordination between the EMC, the multipass translocon, and Sec61 for the biogenesis of diverse membrane proteins in human cells.

哺乳动物的膜蛋白具有重要的生理功能,这些功能依赖于它们在内质网(ER)中的准确插入和折叠。通过正向和阵列遗传筛选,我们系统地研究了一系列膜蛋白的生物发生过程,其中包括几种 G 蛋白偶联受体(GPCR)。我们观察到插入酶、ER 膜蛋白复合物(EMC)的核心作用,并开发了一种双导向方法来鉴定 EMC 的遗传修饰因子。我们发现,多通道转座子的一个组成部分--Sec61(BOS)复合物的背面是 EMC 的一个物理和遗传互作因子。对 EMC⋅BOS 整体复合物的功能和结构分析表明,GPCR 可溶性结构域的特征决定了其生物生成途径。与现有模型不同的是,没有一种插入酶能处理所有底物。相反,我们提出了一个统一的模型,用于协调 EMC、多通道转座子和 Sec61 在人类细胞中多种膜蛋白的生物生成。
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引用次数: 0
Members of an array of zinc-finger proteins specify distinct Hox chromatin boundaries 锌指蛋白阵列的成员指定了不同的 Hox 染色质边界
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.molcel.2024.08.007
Havva Ortabozkoyun, Pin-Yao Huang, Edgar Gonzalez-Buendia, Hyein Cho, Sang Y. Kim, Aristotelis Tsirigos, Esteban O. Mazzoni, Danny Reinberg

Partitioning of repressive from actively transcribed chromatin in mammalian cells fosters cell-type-specific gene expression patterns. While this partitioning is reconstructed during differentiation, the chromatin occupancy of the key insulator, CCCTC-binding factor (CTCF), is unchanged at the developmentally important Hox clusters. Thus, dynamic changes in chromatin boundaries must entail other activities. Given its requirement for chromatin loop formation, we examined cohesin-based chromatin occupancy without known insulators, CTCF and Myc-associated zinc-finger protein (MAZ), and identified a family of zinc-finger proteins (ZNFs), some of which exhibit tissue-specific expression. Two such ZNFs foster chromatin boundaries at the Hox clusters that are distinct from each other and from MAZ. PATZ1 was critical to the thoracolumbar boundary in differentiating motor neurons and mouse skeleton, while ZNF263 contributed to cervicothoracic boundaries. We propose that these insulating activities act with cohesin, alone or combinatorially, with or without CTCF, to implement precise positional identity and cell fate during development.

哺乳动物细胞中抑制性染色质与活性转录染色质的分离促进了细胞类型特异性基因表达模式的形成。虽然这种分区在分化过程中会重建,但在对发育有重要意义的 Hox 簇上,关键绝缘体 CCCTC 结合因子(CTCF)的染色质占位却没有改变。因此,染色质边界的动态变化必须包含其他活动。考虑到染色质环形成的需要,我们在没有已知绝缘体 CTCF 和 Myc 相关锌指蛋白(MAZ)的情况下研究了基于粘合蛋白的染色质占位,并发现了锌指蛋白家族(ZNFs),其中一些表现出组织特异性表达。其中两个 ZNFs 在 Hox 簇上促进染色质边界的形成,这两个 ZNFs 彼此不同,也不同于 MAZ。在运动神经元和小鼠骨骼分化过程中,PATZ1 对胸腰椎边界至关重要,而 ZNF263 则对颈胸椎边界做出了贡献。我们认为,这些绝缘活动与凝聚素一起,单独或组合、有或没有 CTCF,在发育过程中实现了精确的位置认同和细胞命运。
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引用次数: 0
Consecutive palmitoylation and phosphorylation orchestrates NLRP3 membrane trafficking and inflammasome activation 连续棕榈酰化和磷酸化协调了 NLRP3 的膜贩运和炎症小体的激活
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.molcel.2024.08.001
Li Nie, Chenjie Fei, Yizeng Fan, Fabin Dang, Ziyue Zhao, Tingfang Zhu, Xiangyu Wu, Ting Dai, Arumugam Balasubramanian, Jing Pan, Yang Hu, Hongbo R. Luo, Wenyi Wei, Jiong Chen

NLRP3 inflammasome activation, essential for cytokine secretion and pyroptosis in response to diverse stimuli, is closely associated with various diseases. Upon stimulation, NLRP3 undergoes subcellular membrane trafficking and conformational rearrangements, preparing itself for inflammasome assembly at the microtubule-organizing center (MTOC). Here, we elucidate an orchestrated mechanism underlying these ordered processes using human and murine cells. Specifically, NLRP3 undergoes palmitoylation at two sites by palmitoyl transferase zDHHC1, facilitating its trafficking between subcellular membranes, including the mitochondria, trans-Golgi network (TGN), and endosome. This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. Consistently, Zdhhc1-deficiency mitigated LPS-induced inflammation and conferred protection against mortality in mice. Altogether, our findings provide valuable insights into the regulation of NLRP3 membrane trafficking and inflammasome activation, governed by palmitoylation and phosphorylation events.

NLRP3 炎症小体的活化对细胞因子的分泌和对各种刺激的反应中的热变态反应至关重要,它与各种疾病密切相关。受到刺激后,NLRP3 会进行亚细胞膜转运和构象重排,为在微管组织中心(MTOC)组装炎性体做好准备。在这里,我们利用人类和鼠类细胞阐明了这些有序过程的协调机制。具体来说,NLRP3 通过棕榈酰转移酶 zDHHC1 在两个位点进行棕榈酰化,促进其在线粒体、跨高尔基网络(TGN)和内质体等亚细胞膜之间的迁移。这种动态贩运最终导致 NLRP3 定位到 MTOC,在 MTOC 中,LATS1/2(在引物过程中被预先招募到 MTOC)使 NLRP3 磷酸化,进一步促进其与 NIMA 相关激酶 7(NEK7)的相互作用,最终导致 NLRP3 的完全活化。同样,Zdhhc1缺陷可减轻LPS诱导的炎症,并保护小鼠免于死亡。总之,我们的研究结果为了解棕榈酰化和磷酸化事件对 NLRP3 膜贩运和炎性体活化的调控提供了宝贵的见解。
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引用次数: 0
Nuclear PKM2 binds pre-mRNA at folded G-quadruplexes and reveals their gene regulatory role 核 PKM2 与折叠 G 型四联体的前核糖核酸结合并揭示其基因调控作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1016/j.molcel.2024.07.025

Nuclear localization of the metabolic enzyme PKM2 is widely observed in various cancer types. We identify nuclear PKM2 as a non-canonical RNA-binding protein (RBP) that specifically interacts with folded RNA G-quadruplex (rG4) structures in precursor mRNAs (pre-mRNAs). PKM2 occupancy at rG4s prevents the binding of repressive RBPs, such as HNRNPF, and promotes the expression of rG4-containing pre-mRNAs (the “rG4ome”). We observe an upregulation of the rG4ome during epithelial-to-mesenchymal transition and a negative correlation of rG4 abundance with patient survival in different cancer types. By preventing the nuclear accumulation of PKM2, we could repress the rG4ome in triple-negative breast cancer cells and reduce migration and invasion of cancer cells in vitro and in xenograft mouse models. Our data suggest that the balance of folded and unfolded rG4s controlled by RBPs impacts gene expression during tumor progression.

在各种癌症类型中广泛观察到代谢酶 PKM2 的核定位。我们发现核PKM2是一种非典型RNA结合蛋白(RBP),它能与前体mRNA(pre-mRNA)中折叠的RNA G-四重链(rG4)结构发生特异性相互作用。PKM2 在 rG4s 上的占据阻止了抑制性 RBPs(如 HNRNPF)的结合,并促进了含有 rG4 的前 mRNA("rG4ome")的表达。我们观察到,在上皮细胞向间质转化过程中,rG4ome 会上调,而在不同癌症类型中,rG4 的丰度与患者的存活率呈负相关。通过阻止 PKM2 的核积累,我们可以抑制三阴性乳腺癌细胞中的 rG4ome,并减少体外和异种移植小鼠模型中癌细胞的迁移和侵袭。我们的数据表明,RBPs控制的折叠和未折叠rG4s的平衡会影响肿瘤进展过程中的基因表达。
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引用次数: 0
A liquid-like coat mediates chromosome clustering during mitotic exit 液态外衣在有丝分裂过程中介导染色体聚集
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1016/j.molcel.2024.07.022

The individualization of chromosomes during early mitosis and their clustering upon exit from cell division are two key transitions that ensure efficient segregation of eukaryotic chromosomes. Both processes are regulated by the surfactant-like protein Ki-67, but how Ki-67 achieves these diametric functions has remained unknown. Here, we report that Ki-67 radically switches from a chromosome repellent to a chromosome attractant during anaphase in human cells. We show that Ki-67 dephosphorylation during mitotic exit and the simultaneous exposure of a conserved basic patch induce the RNA-dependent formation of a liquid-like condensed phase on the chromosome surface. Experiments and coarse-grained simulations support a model in which the coalescence of chromosome surfaces, driven by co-condensation of Ki-67 and RNA, promotes clustering of chromosomes. Our study reveals how the switch of Ki-67 from a surfactant to a liquid-like condensed phase can generate mechanical forces during genome segregation that are required for re-establishing nuclear-cytoplasmic compartmentalization after mitosis.

有丝分裂早期染色体的个体化和退出细胞分裂时染色体的聚集是确保真核染色体有效分离的两个关键转变过程。这两个过程都受表面活性剂样蛋白 Ki-67 的调控,但 Ki-67 是如何实现这些截然相反的功能的一直是个未知数。在这里,我们报告了 Ki-67 在人体细胞的无丝分裂过程中从染色体排斥者彻底转变为染色体吸引者。我们发现,在有丝分裂后期,Ki-67 去磷酸化,同时暴露出一个保守的基本斑块,诱导染色体表面形成一个依赖于 RNA 的液态凝聚相。实验和粗粒度模拟支持这样一个模型:在Ki-67和RNA共同凝结的驱动下,染色体表面的凝聚促进了染色体的聚集。我们的研究揭示了在基因组分离过程中,Ki-67从表面活化剂转变为液态凝聚相如何产生机械力,而这种机械力是有丝分裂后重建核-细胞质区隔所必需的。
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引用次数: 0
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Molecular Cell
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