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A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis RFC在pcna介导的过程DNA合成中的非催化作用
IF 64.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-28 DOI: 10.1016/j.cell.2025.12.029
Gabriella N.L. Chua, Emily C. Beckwitt, Victoria Miller-Browne, Olga Yurieva, Dan Zhang, Bryce J. Katch, Nina Y. Yao, John W. Watters, Kaitlin Abrantes, Ryogo Funabiki, Xiaolan Zhao, Michael E. O’Donnell, Shixin Liu
The ring-shaped sliding clamp proliferating cell nuclear antigen (PCNA) enables DNA polymerases to perform processive DNA synthesis during replication and repair. The loading of PCNA onto DNA is catalyzed by the ATPase clamp-loader replication factor C (RFC). Using a single-molecule platform to visualize the dynamic interplay between PCNA and RFC on DNA, we unexpectedly discovered that RFC continues to associate with PCNA after loading, contrary to the conventional view. Functionally, this clamp-loader/clamp (CLC) complex is required for processive DNA synthesis by polymerase ẟ (Polẟ), as the PCNA-Polẟ assembly is inherently unstable. This architectural role of RFC is dependent on the BRCA1 C-terminal homology (BRCT) domain of Rfc1, and mutation of its DNA-binding residues causes sensitivity to genotoxic stress in vivo. We further showed that flap endonuclease I (FEN1) can also stabilize the PCNA-Polẟ interaction and mediate robust synthesis. Overall, our work revealed that, beyond their canonical enzymatic functions, PCNA-binding proteins harbor non-catalytic functions important for DNA replication and genome maintenance.
环状滑动钳增殖细胞核抗原(PCNA)使DNA聚合酶在复制和修复过程中进行DNA合成。PCNA装载到DNA上是由atp酶夹装器复制因子C (RFC)催化的。利用单分子平台可视化DNA上PCNA和RFC之间的动态相互作用,我们意外地发现RFC在加载后继续与PCNA结合,这与传统观点相反。在功能上,这种夹夹加载器/夹夹(CLC)复合体是聚合酶ẟ (Polẟ)进行DNA合成所必需的,因为PCNA-Polẟ组装本身是不稳定的。RFC的这种结构作用依赖于RFC的BRCA1 c -末端同源性(BRCT)结构域,其dna结合残基的突变导致体内对基因毒性应激的敏感性。我们进一步发现皮瓣内切酶I (FEN1)也可以稳定PCNA-Polẟ相互作用并介导稳健的合成。总的来说,我们的工作表明,除了它们典型的酶功能外,pcna结合蛋白还具有对DNA复制和基因组维持重要的非催化功能。
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引用次数: 0
PIKFYVE inhibition mitigates disease in models of diverse forms of ALS 抑制PIKFYVE可减轻多种ALS模型的疾病
IF 64.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-24 DOI: 10.1016/j.cell.2026.01.004
Shu-Ting Hung, Gabriel R. Linares, Wen-Hsuan Chang, Yunsun Eoh, Gopinath Krishnan, Stacee Mendonca, Sarah Hong, Yingxiao Shi, Manuel Santana, Chuol Kueth, Samantha Macklin-Isquierdo, Sarah Perry, Sarah Duhaime, Claudia Maios, Jonathan Chang, Joscany Perez, Alexander Couto, Jesse Lai, Yichen Li, Samuel V. Alworth, Justin K. Ichida
(Cell 186, 786–802.e1–e15; February 16, 2023)
(Cell 186, 786-802.e1-e15; 2023年2月16日)
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引用次数: 0
Can H5N1 avian influenza in dairy cattle be contained in the US? H5N1禽流感在美国能否得到控制?
IF 64.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-23 DOI: 10.1016/j.cell.2025.12.033
Jonathan E. Pekar, Alvin Crespo-Bellido, Philippe Lemey, Andrew S. Bowman, Thomas P. Peacock, Jennine N. Ochoa, Andrew Rambaut, Oliver G. Pybus, Michael Worobey, Martha I. Nelson
{"title":"Can H5N1 avian influenza in dairy cattle be contained in the US?","authors":"Jonathan E. Pekar, Alvin Crespo-Bellido, Philippe Lemey, Andrew S. Bowman, Thomas P. Peacock, Jennine N. Ochoa, Andrew Rambaut, Oliver G. Pybus, Michael Worobey, Martha I. Nelson","doi":"10.1016/j.cell.2025.12.033","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.033","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"119 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mechanisms of HSV-1 helicase-primase inhibition and replication fork complex assembly. HSV-1解旋酶-引物酶抑制机制及复制叉复合体组装。
IF 42.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-22 Epub Date: 2025-12-29 DOI: 10.1016/j.cell.2025.11.041
Zishuo Yu, Pradeep Sathyanarayana, Cong Liu, Joel M J Tan, Pan Yang, Biswajit Das, Side Hu, Xiaoyi Fan, Chenggong Ji, Sandra K Weller, Mrinal Shekhar, Donald M Coen, Philip J Kranzusch, Joseph J Loparo, Jonathan Abraham

Herpesviruses are widespread double-stranded DNA viruses that establish lifelong latency and cause various diseases. Although DNA-polymerase-targeting antivirals are effective, increasing drug resistance underscores the need for alternatives. Helicase-primase inhibitors (HPIs) are promising antivirals, but their mechanisms of action are poorly defined. Furthermore, how the helicase-primase (H/P) complex and DNA polymerase coordinate genome replication is not well understood for herpesviruses. Here, we report cryo-electron microscopy (cryo-EM) structures of the herpes simplex virus 1 H/P complex bound to HPIs, showing that these lock the H/P complex in an inactive state. Single-molecule assays reveal that HPIs cause H/P complexes to pause in unwinding activity on DNA. The structure of an HPI-bound replication fork complex, comprising the H/P complex (UL5, UL52, and UL8) and the polymerase holoenzyme (UL30 and UL42), reveals a previously uncharacterized interface bridging these complexes. These findings provide a structural framework for understanding herpesvirus replisome assembly and advancing inhibitor development.

疱疹病毒是一种广泛存在的双链DNA病毒,具有终生潜伏期,可引起多种疾病。尽管靶向dna聚合酶的抗病毒药物是有效的,但不断增加的耐药性强调了寻找替代药物的必要性。解旋酶引物酶抑制剂(hpi)是一种很有前途的抗病毒药物,但其作用机制尚不明确。此外,解旋酶-引物酶(H/P)复合体和DNA聚合酶如何协调疱疹病毒的基因组复制尚不清楚。在这里,我们报告了与hpi结合的单纯疱疹病毒1 H/P复合物的冷冻电镜结构,显示这些将H/P复合物锁定在非活性状态。单分子分析显示hpi导致H/P复合物在DNA上的解绕活性暂停。hpi结合的复制叉复合体的结构,包括H/P复合体(UL5, UL52和UL8)和聚合酶全酶(UL30和UL42),揭示了一个以前未被表征的连接这些复合体的界面。这些发现为理解疱疹病毒复制体组装和推进抑制剂开发提供了一个结构框架。
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引用次数: 0
A two-tier framework for responsible research on human embryo models 负责任的人类胚胎模型研究的两层框架
IF 64.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-22 DOI: 10.1016/j.cell.2025.12.006
Alejandro De Los Angeles, Tim Bayne, Nissim Benvenisty, Hongkui Deng, Misao Fujita, Weizhi Ji, Stephen Latham, Tianqing Li, Pentao Liu, Yuin-Han Loh, Jeantine Lunshof, Duanqing Pei, Nam Pho, José C.R. Silva, Timothy Theodore Ka Ki Tam, Tan Tao, Alan Trounson, Shao Xu, Leqian Yu, Julian Koplin, Alan Regenberg, Kiminobu Sugaya, Julian Savulescu, Magdalena Zernicka-Goetz, Robin Lovell-Badge
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引用次数: 0
Fibroblasts of disparate developmental origins harbor anatomically variant scarring potential 不同发育起源的成纤维细胞具有解剖学上不同的瘢痕形成潜力
IF 64.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-22 DOI: 10.1016/j.cell.2025.12.014
Michelle F. Griffin, Dayan J. Li, Kellen Chen, Jennifer B.L. Parker, Jason L. Guo, Seungsoo Kim, Katerina Kraft, Mauricio Downer, Annah G. Morgan, Maxwell M. Kuhnert, Serena L. Jing, Hanqi Yao, Caleb Valencia, Asha Cotterell, Michael Januszyk, Geoffrey C. Gurtner, Howard Y. Chang, Joanna Wysocka, Derrick C. Wan, Michael T. Longaker
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引用次数: 0
Discoveries beyond molecular mimicry describe how EBV drives multiple sclerosis 分子模拟之外的发现描述了EBV如何驱动多发性硬化症
IF 64.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-22 DOI: 10.1016/j.cell.2025.12.047
Lawrence Steinman, Scott S. Zamvil
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引用次数: 0
MYC binding to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids MYC结合新生RNA抑制先天免疫信号通过r环衍生的RNA- dna杂交
IF 64.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-22 DOI: 10.1016/j.cell.2025.12.019
Leonie Uhl, Amel Aziba, Sinah Löbbert, Timothy Russell, Bastian Krenz, Francisco Montesinos, Toshitha Kannan, Omkar R. Valanju, Christina Schülein-Völk, Tim de Martines, Michael Bolz, Daniel Fleischhauer, Giacomo Cossa, Theresa Endres, Daniel Solvie, Peter Gallant, Andreas Rosenwald, Hans M. Maric, Dimitrios Papadopoulos, Seychelle M. Vos, Martin Eilers
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引用次数: 0
Hepatic adaptation to chronic metabolic stress primes tumorigenesis. 肝脏对慢性代谢应激的适应导致肿瘤的发生。
IF 42.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-22 Epub Date: 2025-12-22 DOI: 10.1016/j.cell.2025.11.031
Constantine N Tzouanas, Jessica E S Shay, Marc S Sherman, Adam J Rubin, Benjamin E Mead, Tyler T Dao, Junyan Tao, Brandon M Lehrich, George Eng, Jeffrey Patterson-Fortin, Titus Butzlaff, Miyeko D Mana, Kellie E Kolb, Chad Walesky, Brian J Pepe-Mooney, Colton J Smith, Sanjay M Prakadan, Michelle L Ramseier, Yuzhou Evelyn Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L Winston, Woo-Jeong Jeong, Katherine J Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Satdarshan P Monga, Georg M Lauer, Wolfram Goessling, Ömer H Yilmaz, Alex K Shalek

During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress' functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells' early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core actionable mechanisms.

在慢性压力下,细胞必须支持组织功能和自身生存。肝细胞具有代谢、合成和解毒作用,但慢性营养失衡可诱导肝细胞死亡并诱发代谢功能障碍相关的脂肪性肝炎(MASH,以前称为NASH)。尽管先前的研究发现了应激诱导的肝细胞死亡驱动因素,但慢性应激对存活细胞的功能影响仍不清楚。通过跨物种纵向单细胞多组学,我们发现持续的压力驱动非转化肝细胞的预后发育和癌症相关程序,同时降低其成熟的功能特征。创建综合计算方法,我们确定并实验验证干扰肝细胞功能平衡的主要调节因子,在压力下增加增殖,并直接引发未来的肿瘤发生。通过对人体组织微阵列空间转录组学的地理回归,我们揭示了空间结构的多细胞群落和形成应激反应的信号相互作用。我们的工作揭示了细胞对慢性应激的早期解决方案如何能够启动未来的肿瘤发生和结果,统一了围绕核心可操作机制的多种细胞功能障碍模式。
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引用次数: 0
Butyrolactol A enhances caspofungin efficacy via flippase inhibition in drug-resistant fungi. 丁唑醇A通过抑制耐药真菌的翻转酶增强caspofungin的疗效。
IF 42.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-22 Epub Date: 2025-12-31 DOI: 10.1016/j.cell.2025.11.036
Xuefei Chen, H Diessel Duan, Michael J Hoy, Kalinka Koteva, Michaela Spitzer, Allison K Guitor, Emily Puumala, Aline A Fiebig, Guanggan Hu, Bonnie Yiu, Sommer Chou, Zhuyun Bian, Yeseul Choi, Amelia Bing Ya Guo, Wenliang Wang, Sheng Sun, Nicole Robbins, Anna Floyd Averette, Michael A Cook, Ray Truant, Lesley T MacNeil, Eric D Brown, James W Kronstad, Brian K Coombes, Leah E Cowen, Joseph Heitman, Huilin Li, Gerard D Wright

Fungal infections cause millions of deaths annually and are challenging to treat due to limited therapeutic options and rising resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while Candida auris, a notorious global threat, is also increasingly resistant. We performed a natural product screen to rescue caspofungin fungicidal activity against Cryptococcus neoformans H99 and identified butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including multidrug-resistant C. auris. Mode-of-action studies reveal that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1-butyrolactol A complex reveals that the flippase is trapped in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies lipid flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.

真菌感染每年造成数百万人死亡,由于治疗选择有限和耐药性上升,治疗具有挑战性。隐球菌对最新一代的抗真菌药物棘白菌素具有内在耐药性,而臭名昭著的全球威胁——耳念珠菌的耐药性也越来越强。我们进行了天然产物筛选,以恢复刺白菌素对新型隐球菌H99的杀真菌活性,并鉴定出丁唑醇a,它可以恢复刺白菌素对耐药真菌病原体的功效,包括耐多药的金黄色葡萄球菌。作用模式研究表明,丁醇A抑制磷脂翻转酶Apt1-Cdc50,阻断磷脂转运。apt1 -丁醇A配合物的低温电子显微镜分析显示,翻转酶被困在一个死端状态。Apt1抑制破坏膜不对称、囊泡运输和细胞骨架组织,从而增强棘白菌素的摄取和效力。本研究确定了脂质翻转酶作为有希望的抗真菌靶点,并展示了重新研究天然产物以扩大抗真菌武器库和对抗耐药性的潜力。
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