Molecular Cell最新文献_第7页

Molecular mechanism of HUWE1-HAPSTR1-USP7-mediated ubiquitin chain amplification on nuclear proteins huwe1 - hapstr1 - usp7介导的核蛋白泛素链扩增的分子机制

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 DOI: 10.1016/j.molcel.2026.08.016

Stanislau Yatskevich,Jugal Mohapatra,Rana Mroue,Lilian Phu,Alexander Leitner,Caleigh M. Azumaya,Richard Vandlen,Tommy K. Cheung,Tik Hang Soong,Christopher M. Rose,Alessandro Ori,Claudio Ciferri,Szymon Juszkiewicz

{"title":"Molecular mechanism of HUWE1-HAPSTR1-USP7-mediated ubiquitin chain amplification on nuclear proteins","authors":"Stanislau Yatskevich,Jugal Mohapatra,Rana Mroue,Lilian Phu,Alexander Leitner,Caleigh M. Azumaya,Richard Vandlen,Tommy K. Cheung,Tik Hang Soong,Christopher M. Rose,Alessandro Ori,Claudio Ciferri,Szymon Juszkiewicz","doi":"10.1016/j.molcel.2026.08.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.016","url":null,"abstract":"Rapid protein turnover is essential for cellular stress adaptation. HUWE1 (HECT, UBA, and WWE domain containing 1), a large HECT-type E3 ligase, regulates many short-lived stress-responsive proteins, yet the mechanisms underlying its substrate selectivity remain unclear. Here, we reveal that HUWE1 functions as a ubiquitin chain amplifier that captures pre-ubiquitinated substrates and amplifies the degradation signal by assembling long ubiquitin chains containing K11-K48 branch points, a process regulated by its partners HUWE1-associated protein stress response 1 (HAPSTR1) and USP7 (ubiquitin-specific-processing protease 7). Structural and biochemical analyses show that HAPSTR1 engages HUWE1’s ubiquitin-binding motifs to drive nuclear import and modulate substrate recruitment. A cryo-EM structure of the HUWE1-USP7 complex reveals a bidirectional regulatory mechanism: HUWE1 activates USP7’s catalytic activity, while USP7 modulates HUWE1 conformational states. Global proteomic analyses demonstrate that this axis drives extensive remodeling of the short-lived nuclear proteome. These findings establish the HUWE1-HAPSTR1-USP7 complex as a key ubiquitin code modifier, providing a molecular rationale for HUWE1 dysregulation in neurodevelopmental disorders and cancer.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"46 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148980624","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

CONCR lncRNA organizes a 3'-end structural domain that engages DDX11 for DNA replication and sister chromatid cohesion. CONCR lncRNA组织一个3'端结构域，参与DDX11进行DNA复制和姐妹染色单体内聚。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 Epub Date: 2026-08-28 DOI: 10.1016/j.molcel.2026.08.004

Andrés López-Perrote, Eva María Martín-Cuevas, José Antonio Mérida-Cerro, Clara Aicart-Ramos, Ana González-Corpas, Jovanna González, Johanne Le Coq, Jasminka Boskovic, Isabel Chillón, Oscar Llorca, Fernando Moreno-Herrero, Maite Huarte

{"title":"CONCR lncRNA organizes a 3'-end structural domain that engages DDX11 for DNA replication and sister chromatid cohesion.","authors":"Andrés López-Perrote, Eva María Martín-Cuevas, José Antonio Mérida-Cerro, Clara Aicart-Ramos, Ana González-Corpas, Jovanna González, Johanne Le Coq, Jasminka Boskovic, Isabel Chillón, Oscar Llorca, Fernando Moreno-Herrero, Maite Huarte","doi":"10.1016/j.molcel.2026.08.004","DOIUrl":"10.1016/j.molcel.2026.08.004","url":null,"abstract":"CONCR (DDX11-AS1) is a long noncoding RNA (lncRNA) necessary for the establishment of sister chromatid cohesion. Despite its activity, whether it contains structural elements essential for its function remains unknown. We determined CONCR structural organization and its functional relevance by integrating selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP), atomic force microscopy (AFM), evolutionary analyses, cryo-electron microscopy (cryo-EM), and cellular genetic studies. We found that CONCR molecular topology is modular, with highly structured domains connected by flexible linkers. A large 3'-end domain is responsible for binding to DDX11 helicase, can trigger DDX11 ATPase activity, and is essential for proper DNA replication and sister chromatid cohesion. This 3' end comprises two helical arms connecting two multiway junctions with structural motifs conserved among all primate groups and required for DDX11 binding and sister chromatid cohesion. Our results highlight the critical role of RNA structure in CONCR function, with a highly structured 3'-end domain acting as a loading and activation platform for DDX11 helicase.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3673-3690.e12"},"PeriodicalIF":16.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850610","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

Intragenomic homologs with distinct phase behaviors broaden the range of cellular stress responses. 具有不同相行为的基因组内同源物拓宽了细胞应激反应的范围。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-17 Epub Date: 2026-08-28 DOI: 10.1016/j.molcel.2026.08.002

Jian Guan, Bikash R Sahoo, Tyler S Brant, Pavithra Mahadevan, Antonia Brooks, Shyamal Mosalaganti, James C A Bardwell, Ursula Jakob

{"title":"Intragenomic homologs with distinct phase behaviors broaden the range of cellular stress responses.","authors":"Jian Guan, Bikash R Sahoo, Tyler S Brant, Pavithra Mahadevan, Antonia Brooks, Shyamal Mosalaganti, James C A Bardwell, Ursula Jakob","doi":"10.1016/j.molcel.2026.08.002","DOIUrl":"10.1016/j.molcel.2026.08.002","url":null,"abstract":"Intragenomic homologs are widespread, but their physiological roles are often masked by redundancy. Histone-like nucleoid structuring protein (H-NS), a nucleoid-associated protein in Gram-negative bacteria, typically coexists with homologs like StpA, whose functions are obscured by a lack of strong phenotypes. We demonstrate here that the interaction between H-NS and StpA fine-tunes the physico-chemical properties of nucleoid-associated compartments. Although H-NS forms dynamic condensates in vitro, StpA assembles into stable insoluble fibrils. However, together the two proteins form liquid-like droplets, whose fluidity and stability are tunable by their relative stoichiometry. By increasing the levels of StpA over H-NS, bacteria stabilize heterochromatin-associated compartments, thereby preserving gene repression and optimizing bacterial growth under stress. Structural differences at these proteins' dimerization sites help explain their distinct phase behaviors. Our findings reveal a paradigm in which intragenomic homologs that are positioned at the opposite ends of the phase spectrum can fine-tune subcellular organization to promote survival in fluctuating environments.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3774-3788.e7"},"PeriodicalIF":16.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850785","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

Cohesin preservation across mitosis contributes to restart transcription via Cdk9-mediated activation of RNAPol2 通过cdk9介导的RNAPol2激活，有丝分裂中的内聚蛋白保存有助于重启转录

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-16 DOI: 10.1016/j.molcel.2026.08.021

Aida Contreras-Pérez,Héctor Espinosa,Estrella Isabel Sayago,Avik Basu,Andrew Emili,Michael D. Blower,Carlos Perea-Resa

{"title":"Cohesin preservation across mitosis contributes to restart transcription via Cdk9-mediated activation of RNAPol2","authors":"Aida Contreras-Pérez,Héctor Espinosa,Estrella Isabel Sayago,Avik Basu,Andrew Emili,Michael D. Blower,Carlos Perea-Resa","doi":"10.1016/j.molcel.2026.08.021","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.021","url":null,"abstract":"Cohesin organizes 3D genome architecture yet its acute depletion in vitro minimally affects transcription, leaving its regulatory role puzzling. We hypothesized that cohesin function is relevant when first encounters chromatin after mitosis. Using in vivo labeling and cell-cycle synchronization in human cells, we demonstrate that cohesin complexes persist through mitosis. This inherited pool dominates over newly translated cohesin during telophase-G1, highlighting the relevance of such transmission. Acute depletion of cohesin Rad21 at mitotic exit impairs the expression of hundreds of genes, mostly downregulated, enriched on functions related to tissue growth and development. Rad21 binds the promoter of this group of genes. Remarkably, we uncover a direct interaction during the M-G1 transition between Rad21 and Cdk9, the kinase component of transcription elongation factor b (pTEFb) complex. Rad21 loss impairs Cdk9 chromatin association, reducing active-elongating RNAPol2 at down-regulated genes. Overall, preserving cohesin across mitosis enables post-mitotic transcriptional reactivation via Cdk9, establishing tissue-specific expression programs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"150 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973289","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

Nuclear body assembly by a viral repeat RNA promotes Kaposi’s sarcoma-associated herpesvirus gene expression 病毒重复RNA的核体组装促进卡波西氏肉瘤相关疱疹病毒基因的表达

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-16 DOI: 10.1016/j.molcel.2026.08.022

Mariel Kleer,Rory P. Mulloy,Maxwell P. Bui-Marinos,Michael J. Johnston,Morgan F. Khan,David C. Schriemer,Jennifer A. Corcoran

引用次数: 0

A dual-module ECAS complex couples transcription elongation and RNA processing 双模块ECAS复合体将转录延伸和RNA加工结合在一起

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-16 DOI: 10.1016/j.molcel.2026.08.019

Ying Xiang,Honghong Wang,Zhinang Yin,Ruijing Xiao,Zemin Song,Rui Lu,Rong Dai,Jiaqin Ye,Conghui Li,Yali Cui,Mengxuan Wang,Junhui Lv,Qiuzi Li,Fuqi Wang,Zhuoshi Li,Kaiwen Zhang,Yiming Zhang,Di Wu,Pingping Fang,Kaiwei Liang

{"title":"A dual-module ECAS complex couples transcription elongation and RNA processing","authors":"Ying Xiang,Honghong Wang,Zhinang Yin,Ruijing Xiao,Zemin Song,Rui Lu,Rong Dai,Jiaqin Ye,Conghui Li,Yali Cui,Mengxuan Wang,Junhui Lv,Qiuzi Li,Fuqi Wang,Zhuoshi Li,Kaiwen Zhang,Yiming Zhang,Di Wu,Pingping Fang,Kaiwei Liang","doi":"10.1016/j.molcel.2026.08.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.019","url":null,"abstract":"Faithful gene expression requires coordination between RNA polymerase II elongation and co-transcriptional RNA processing, yet the chromatin-associated assemblies supporting this coupling remain incompletely defined. Using native chromatin proteomics in human cells, we identify ECAS (elongation complex associated with splicing), a bipartite assembly linking an elongation module (AFF4-ELL2-EAF1) to a U2 snRNP-associated intron binding complex. ECAS occupies promoter-proximal chromatin and is molecularly distinct from canonical P-TEFb-containing super elongation complex (SEC). Acute perturbation of Aquarius (AQR)/XAB2-dependent ECAS functions impairs productive gene-body elongation without altering pause release, increases intron retention, and preferentially affects long genes. AQR loss also reduces capping-factor recruitment and nascent 5′ capping and increases promoter-proximal accumulation of cleavage/polyadenylation and RNA exosome factors. In mouse hematopoietic cells, Aqr is highly expressed, and its perturbation profoundly impairs leukemia initiation, maintenance, and leukemia stem cell function in MLL-rearranged leukemia. Together, these findings establish ECAS as a chromatin-associated assembly that couples productive elongation with RNA processing.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"54 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973455","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

5-Azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia 5-氮胞嘧啶通过5-甲基胞嘧啶对白血病染色质相关RNA的耗竭诱导细胞毒性

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-15 DOI: 10.1016/j.molcel.2026.08.018

Boyang Gao,Ying Li,Xinyuan Ma,Long Zhao,Zhongyu Zou,Juyeong Hong,Junhong Xiang,Xiaoyang Dou,Feng-Chun Yang,Mingjiang Xu,Chuan He

{"title":"5-Azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia","authors":"Boyang Gao,Ying Li,Xinyuan Ma,Long Zhao,Zhongyu Zou,Juyeong Hong,Junhong Xiang,Xiaoyang Dou,Feng-Chun Yang,Mingjiang Xu,Chuan He","doi":"10.1016/j.molcel.2026.08.018","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.018","url":null,"abstract":"5-Azacytidine (5-azaC) is a DNA hypomethylating agent clinically used in myeloid malignancies. As a ribonucleoside analogue, 5-azaC incorporates more readily into nascent RNA than DNA. Here, we demonstrate that RNA 5-methylcytosine (m5C) depletion by 5-azaC treatment, particularly at early time points, is sufficient to induce leukemia cell death. In contrast to its DNA demethylation function, the RNA-dependent effects of 5-azaC lead to transcriptional repression, disrupting genes involved in cell-cycle regulation and DNA repair. Mechanistically, depletion of m5C by 5-azaC in chromatin-associated RNA (caRNA) disrupts the MBD6-mediated H2AK119ub deubiquitination. This also impairs SRSF2 recruitment and the downstream H3K27ac deposition by p300. Consistently, loss of the caRNA methyltransferase NSUN2 caused prolonged cell cycle, defective DNA repair, and shifted hematopoietic lineage commitment toward erythropoiesis, mirroring the effects of 5-azaC treatment. Our findings highlight the transcriptional repression by 5-azaC through depleting caRNA m5C, providing additional insights into the mechanism of action for 5-azaC.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"59 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148964347","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

TRiC/CCT chaperonin governs RNA polymerase II activity in the nucleus to support RNA homeostasis TRiC/CCT伴侣蛋白控制RNA聚合酶II在细胞核中的活性，以支持RNA稳态

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-08 DOI: 10.1016/j.molcel.2026.08.015

Zlata Gvozdenov,Anusmita Biswas,Audrey Yi Tyan Peng,Zeno Barcutean,Daniel Gestaut,Judith Frydman,Kevin Struhl,Brian C. Freeman

{"title":"TRiC/CCT chaperonin governs RNA polymerase II activity in the nucleus to support RNA homeostasis","authors":"Zlata Gvozdenov,Anusmita Biswas,Audrey Yi Tyan Peng,Zeno Barcutean,Daniel Gestaut,Judith Frydman,Kevin Struhl,Brian C. Freeman","doi":"10.1016/j.molcel.2026.08.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.015","url":null,"abstract":"Eukaryotic tailless complex polypeptide 1 ring complex/Chaperonin containing tailless complex polypeptide 1 (TRiC/CCT) chaperonin is typically considered a cytosolic machine mediating polypeptide folding and assembly of protein complexes. Here, we investigated the nuclear role of TRiC/CCT. Use of a TRiC/CCT temperature-sensitive allele revealed increased production of nascent RNA leading to the accumulation of noncoding transcripts. TRiC/CCT was associated with RNA polymerase II (RNAPII) in vitro and in vivo, including when bound to DNA. Heat treatment of the TRiC/CCT ts chaperonin stabilized the RNAPII complex association and binding to the actin and tubulin substrates. Expression of the Huntingtin protein Htt correlated with lowered RNA production and a decreased association between the RNAPII and TRiC/CCT complexes. Together, our presented data support a model where TRiC/CCT regulates the global activity of RNAPII in reaction to the status of proteostasis. Overall, our work reveals an avenue by which TRiC/CCT contributes to homeostasis by regulating the activity of nuclear RNAPII.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"37 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148902441","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

HP1α binding creates a local barrier against transcription activation and persists during chromatin decondensation HP1α结合产生一个局部的屏障，阻止转录激活，并在染色质去浓缩过程中持续存在

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-08 DOI: 10.1016/j.molcel.2026.08.013

Robin Weinmann,Arjun Udupa,Jan Fabio Nickels,Tsz Ching Chloe Tang,Anne Rademacher,Lukas Frank,Caroline Knotz,Karsten Rippe

{"title":"HP1α binding creates a local barrier against transcription activation and persists during chromatin decondensation","authors":"Robin Weinmann,Arjun Udupa,Jan Fabio Nickels,Tsz Ching Chloe Tang,Anne Rademacher,Lukas Frank,Caroline Knotz,Karsten Rippe","doi":"10.1016/j.molcel.2026.08.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.013","url":null,"abstract":"Mouse pericentric heterochromatin forms compacted, transcriptionally silent domains, termed chromocenters, that are enriched in heterochromatin protein 1 (HP1). Whether HP1α represses chromocenters by binding locally or by maintaining a phase-separated compartment is unresolved. We investigated this question by recruiting transcriptional activators to mouse fibroblast chromocenters and quantifying repression at a transcription reporter. HP1α established a promoter-proximal barrier that suppressed weaker activators (VP16) but was overcome by stronger ones (VP64-p65-Rta [VPR] and p65). Activator-induced decondensation and transcription occurred without displacing HP1α or H3K9 trimethylation, and HP1α retained its granular distribution and stoichiometric binding dynamics. Multi-color super-resolution imaging revealed spatial segregation of transcribed and HP1α-bound regions at the nanodomain scale. A nanodomain model captured how repeat clusters independently transition between silenced and activated states. These data establish that HP1α and H3K9me3 act through independently switchable nanodomains, accounting for chromocenter regulation without invoking phase separation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"20 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148902440","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

Long-range mRNA folding shapes expression and sequence of bacterial genes 细菌基因的远程mRNA折叠形状、表达和序列

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-08 DOI: 10.1016/j.molcel.2026.08.014

Manraj S. Gill,Isabelle A. Kim,James R. Xue,Yashna Thappeta,James C. Taggart,Gene-Wei Li

引用次数: 0