Molecular Cell最新文献_第10页

Disruption of microhomology-mediated end joining in Ewing sarcoma. Ewing肉瘤中微同源介导的末端连接中断。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-07-21 DOI: 10.1016/j.molcel.2026.06.038

Shuhei Asada, Guangli Zhu, Jithma Prasad Abeykoon, Yutaro Tanaka, Huy Nguyen, Yuna Hirohashi, Divya R Iyer, Nicholas William Ashton, Sirisha Mukkavalli, Martha Velazquez, Lige Jiang, Miles Del Busso, Judith Jebastin Thangaiah, Steven I Robinson, Kalindi Parmar, Eliezer M Van Allen, Riaz Gillani, Geoffrey I Shapiro, Alan D D'Andrea

{"title":"Disruption of microhomology-mediated end joining in Ewing sarcoma.","authors":"Shuhei Asada, Guangli Zhu, Jithma Prasad Abeykoon, Yutaro Tanaka, Huy Nguyen, Yuna Hirohashi, Divya R Iyer, Nicholas William Ashton, Sirisha Mukkavalli, Martha Velazquez, Lige Jiang, Miles Del Busso, Judith Jebastin Thangaiah, Steven I Robinson, Kalindi Parmar, Eliezer M Van Allen, Riaz Gillani, Geoffrey I Shapiro, Alan D D'Andrea","doi":"10.1016/j.molcel.2026.06.038","DOIUrl":"10.1016/j.molcel.2026.06.038","url":null,"abstract":"Ewing sarcoma (EwS) is a group of bone and soft-tissue cancers in children and young adults. Because EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the oncoprotein EWS-FLI1 is likely to be involved in DNA repair. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of Polθ, a critical protein in the MMEJ pathway. Expression of EWS-FLI1 or depletion of EWSR1 causes increased POLQ exon 25 skipping, decreased Polθ expression, impaired MMEJ, and enhanced cellular sensitivity to inhibitors of the Fanconi anemia (FA), homologous recombination (HR), or non-homologous end joining (NHEJ) pathways, through the mechanism of synthetic lethality. Correction of POLQ exon 25 skipping restored Polθ expression and MMEJ activity in EwS. Inhibitors of the FA, HR, or NHEJ pathways may therefore provide a targeted therapy for EwS patients.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3167-3184.e12"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13404124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A splicing twist from Ψ 来自Ψ的拼接扭曲

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 DOI: 10.1016/j.molcel.2026.07.021

Yuan W. Tian,Matthias Soller

引用次数: 0

α-Satellite RNA maintains centromeric cohesion through R-loops. α-卫星RNA通过r环维持着丝粒内聚。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-08-05 DOI: 10.1016/j.molcel.2026.07.023

Lu Yang, Qian Zhang, Zhen Teng, Erin Moran, Zhen Lin, P Todd Stukenberg, Hong Liu

{"title":"α-Satellite RNA maintains centromeric cohesion through R-loops.","authors":"Lu Yang, Qian Zhang, Zhen Teng, Erin Moran, Zhen Lin, P Todd Stukenberg, Hong Liu","doi":"10.1016/j.molcel.2026.07.023","DOIUrl":"10.1016/j.molcel.2026.07.023","url":null,"abstract":"Tandemly repeated satellite DNAs provide the building blocks for centromeres, but whether and how their transcripts regulate chromosome segregation remain poorly defined. Here, we show that human α-satellite RNAs (α-SatRNAs) are required for maintaining centromeric cohesion during mitosis. α-SatRNAs localize to centromeres and physically associate with α-satellite chromatin to form R-loops both in cis and in trans. Disruption of these R-loops by RNase H1 overexpression causes centromeric cohesion defects, phenocopying α-SatRNA knockdown, which can be rescued by the expression of an α-satellite consensus sequence, supporting a major role for α-SatRNA-formed R-loops in centromeric cohesion. Furthermore, ectopic targeting of the cohesion protector Shugoshin (Sgo)1 to centromeric α-SatDNAs largely rescues centromeric cohesion defects caused by α-SatRNA knockdown or RNase H1 overexpression. Our findings reveal a critical pathway comprising α-SatRNAs, R-loops, and Sgo1 in regulating centromeric cohesion, thus providing an important mechanism to explain how satellite transcripts regulate chromosomal stability.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3198-3212.e6"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

METTL3 promotes cell-cycle progression via activation of transcriptional elongation. METTL3通过激活转录延伸促进细胞周期进程。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-07-31 DOI: 10.1016/j.molcel.2026.07.011

Azime Akçaöz-Alasar, Yanhua Wang, Hang Li, Denis Ostapenko, Carlos A Ramírez Parrado, Daniela Villalobos, Wenxue Li, Prajwal C Boddu, Alexander H Nguyen, Hengyi Li, Marcelo Perez-Pepe, Pénélope Darnat, Bünyamin Akgül, Manoj M Pillai, Yansheng Liu, Lilian Kabeche, Claudio R Alarcón

{"title":"METTL3 promotes cell-cycle progression via activation of transcriptional elongation.","authors":"Azime Akçaöz-Alasar, Yanhua Wang, Hang Li, Denis Ostapenko, Carlos A Ramírez Parrado, Daniela Villalobos, Wenxue Li, Prajwal C Boddu, Alexander H Nguyen, Hengyi Li, Marcelo Perez-Pepe, Pénélope Darnat, Bünyamin Akgül, Manoj M Pillai, Yansheng Liu, Lilian Kabeche, Claudio R Alarcón","doi":"10.1016/j.molcel.2026.07.011","DOIUrl":"10.1016/j.molcel.2026.07.011","url":null,"abstract":"Transcriptional elongation undergoes extensive remodeling at mitotic entry, yet how elongation control is integrated into core cell-cycle kinase networks remains unclear. Here, we identify the m6A methyltransferase METTL3 as a direct substrate of the mitotic kinase CDK1 in mammalian cells. CDK1-dependent phosphorylation of METTL3 at Ser43 is sharply induced at mitotic entry and promotes m6A methylation of the noncoding RNA 7SK, resulting in release of positive transcription elongation factor b (P-TEFb) from the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP) complex. This activation of the m6A/7SK/P-TEFb axis facilitates genome-wide clearance of RNA polymerase II and supports timely mitotic progression. Endogenous mutation of METTL3 Ser43 or disruption of 7SK methylation impairs elongation dynamics, delays mitotic exit, and increases chromosome missegregation. These findings integrate RNA methylation into the CDK1-driven mitotic program and reveal a mechanism by which transcriptional elongation is coordinated with chromosome segregation fidelity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3213-3222.e5"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648644","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

Temporal control of macrophage pro-inflammatory phenotype by a biphasic HIF-1α regulatory program. 双相HIF-1α调控程序对巨噬细胞促炎表型的时间控制

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-07-21 DOI: 10.1016/j.molcel.2026.07.001

Gustavo Gastão Davanzo, Guilherme Ribeiro, Douglas Dos-Santos, Marcelo Rodrigues Berçot, Isabella Zaidan, Larissa Menezes Dos Reis, João Victor Virgilio-da-Silva, Bianca Gazieri Castelucci, Paulo Estevão, Wanderson Dourado Souza, Henver S Bruneta, José Luis Fachi, Webster Leonardo Costa, João Nilton Barreto Andrade, Gerson S Profeta, Rodrigo Requião Dias, Natália S Wassano, Lauar de Brito Monteiro, Jessica Aparecida da Silva Pereira, Cristhiane Favero de Aguiar, Monara Kaélle Sérvulo Cruz Angelim, Wilias Greison Santos, Victor Corasolla Carregari, Jonathan Peña, Carlos Alberto de Carvalho Fraga, Marcelo A Mori, Silvio Roberto Consonni, Daniel Martins-de-Souza, Marco Aurélio Ramirez Vinolo, Helder Nakaya, Peter J Murray, Afshin Beheshti, Larissa Dias Cunha, Pedro M Moraes-Vieira

{"title":"Temporal control of macrophage pro-inflammatory phenotype by a biphasic HIF-1α regulatory program.","authors":"Gustavo Gastão Davanzo, Guilherme Ribeiro, Douglas Dos-Santos, Marcelo Rodrigues Berçot, Isabella Zaidan, Larissa Menezes Dos Reis, João Victor Virgilio-da-Silva, Bianca Gazieri Castelucci, Paulo Estevão, Wanderson Dourado Souza, Henver S Bruneta, José Luis Fachi, Webster Leonardo Costa, João Nilton Barreto Andrade, Gerson S Profeta, Rodrigo Requião Dias, Natália S Wassano, Lauar de Brito Monteiro, Jessica Aparecida da Silva Pereira, Cristhiane Favero de Aguiar, Monara Kaélle Sérvulo Cruz Angelim, Wilias Greison Santos, Victor Corasolla Carregari, Jonathan Peña, Carlos Alberto de Carvalho Fraga, Marcelo A Mori, Silvio Roberto Consonni, Daniel Martins-de-Souza, Marco Aurélio Ramirez Vinolo, Helder Nakaya, Peter J Murray, Afshin Beheshti, Larissa Dias Cunha, Pedro M Moraes-Vieira","doi":"10.1016/j.molcel.2026.07.001","DOIUrl":"10.1016/j.molcel.2026.07.001","url":null,"abstract":"Hypoxia-inducible factor 1α (HIF-1α) broadly orchestrates metabolic reprogramming in inflammatory macrophages. However, how HIF-1α shapes the earliest events following activation of pattern recognition receptors and triggers inflammatory responses remain unclear. We found that HIF-1α is functionally active shortly after macrophage inflammatory stimulation via a Rubicon (RUBCN)-NADPH oxidase (NOX2) reactive oxygen species (ROS) circuit, driving glycolysis, cytokine production, and bacterial killing before maximal protein accumulation. Early HIF-1α stabilization primes inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, which subsequently suppresses electron transport chain function and induces mitochondrial dysfunction independently of RUBCN and NOX2. These findings elucidate a temporally coordinated HIF-1α pathway that integrates RUBCN-NOX2 redox signaling to control macrophage inflammation, metabolic adaptation, and antimicrobial defense.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3223-3239.e11"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549829","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

From nucleotides to phospholipids: UCK1’s unexpected role in SARS-CoV-2 membrane remodeling 从核苷酸到磷脂：UCK1在SARS-CoV-2膜重塑中的意外作用

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 DOI: 10.1016/j.molcel.2026.07.029

Yvonne F. Grande,Eva Herker

引用次数: 0

HIF-1α sets the activation tempo of inflammatory macrophages HIF-1α设定炎症性巨噬细胞的激活速度

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 DOI: 10.1016/j.molcel.2026.07.032

Marta Manco,Alessia Zotta,Massimiliano Mazzone

引用次数: 0

Stepwise DNA-unwinding gates TnpB genome-editing activity. 逐步的dna解绕打开了TnpB基因组编辑活性。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-08-05 DOI: 10.1016/j.molcel.2026.07.015

Zehan Zhou, Iren Saffarian-Deemyad, Honglue Shi, Trevor Weiss, Muhammad Moez Ur-Rehman, Kamakshi Vohra, Petr Skopintsev, Peter H Yoon, Marena I Trinidad, Conner J Langeberg, Maris Kamalu, Jasmine Amerasekera, Yuxing Zhou, Erin E Doherty, Kevin D P Aris, Noor Al-Sayyad, Brittney W Thornton, Rachel F Weissman, Kevin M Wasko, Isabel Esain-Garcia, Evan C DeTurk, David F Savage, Steven E Jacobsen, Zev Bryant, Jennifer A Doudna

{"title":"Stepwise DNA-unwinding gates TnpB genome-editing activity.","authors":"Zehan Zhou, Iren Saffarian-Deemyad, Honglue Shi, Trevor Weiss, Muhammad Moez Ur-Rehman, Kamakshi Vohra, Petr Skopintsev, Peter H Yoon, Marena I Trinidad, Conner J Langeberg, Maris Kamalu, Jasmine Amerasekera, Yuxing Zhou, Erin E Doherty, Kevin D P Aris, Noor Al-Sayyad, Brittney W Thornton, Rachel F Weissman, Kevin M Wasko, Isabel Esain-Garcia, Evan C DeTurk, David F Savage, Steven E Jacobsen, Zev Bryant, Jennifer A Doudna","doi":"10.1016/j.molcel.2026.07.015","DOIUrl":"10.1016/j.molcel.2026.07.015","url":null,"abstract":"TnpB is a compact RNA-guided endonuclease and an evolutionary ancestor of CRISPR-Cas12 that offers a promising platform for genome engineering. However, the genome-editing activity of TnpBs remains limited, and its underlying determinants are poorly understood. Here, we used biochemical and single-molecule assays to examine the DNA-unwinding mechanism of Youngiibacter multivorans TnpB (Ymu1 TnpB). DNA unwinding proceeds through a discrete, long-lived, partially unwound intermediate state before reaching a fully unwound open state. The open state forms inefficiently and collapses readily in the absence of negative supercoiling. An optimized variant, H4W-L304F-V305R (Ymu1-WFR), stabilizes formation of both the intermediate and open states, resulting in enhanced DNA cleavage in vitro and increased genome editing in plants. These findings identify the physical basis for the observed minimal activities of natural TnpBs, revealing how stabilizing specific unwinding states enables efficient DNA targeting.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3154-3166.e11"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Legionella pneumophila effector SidL is an adenylyltransferase that modifies the glycolytic intermediate 3-phosphoglycerate. 嗜肺军团菌效应剂SidL是一种腺苷基转移酶，可修饰糖酵解中间体3-磷酸甘油酸。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-07-24 DOI: 10.1016/j.molcel.2026.07.007

Joshua J Black, A Maxwell Burroughs, Edrees H Rashan, Charles R Nosal, Katerina A Romanov, Marco A Catipovic, Catherine Valadez, L Aravind, Kevin G Hicks, Caren L Freel Meyers, Tamara J O'Connor, Matthew G Vander Heiden, Rachel Green

{"title":"The Legionella pneumophila effector SidL is an adenylyltransferase that modifies the glycolytic intermediate 3-phosphoglycerate.","authors":"Joshua J Black, A Maxwell Burroughs, Edrees H Rashan, Charles R Nosal, Katerina A Romanov, Marco A Catipovic, Catherine Valadez, L Aravind, Kevin G Hicks, Caren L Freel Meyers, Tamara J O'Connor, Matthew G Vander Heiden, Rachel Green","doi":"10.1016/j.molcel.2026.07.007","DOIUrl":"10.1016/j.molcel.2026.07.007","url":null,"abstract":"The large effector arsenal of the bacterial pathogen Legionella pneumophila has been a rich source of biochemistry, highlighting the immense diversity of strategies deployed in host-pathogen conflict. Here, we redefine the purported translation inhibitor SidL as an adenylyltransferase that targets a glycolytic metabolite, discovering that it modifies 3-phosphoglycerate with adenosine monophosphate (AMP) to produce the previously unknown molecule 2-AMP-3-phosphoglycerate. When expressed alone in mammalian cells, SidL adenylates 3-phosphoglycerate, disrupts glycolysis, and blocks the nutrient-responsive translation regulator mTORC1, which we propose indirectly causes translation inhibition. Moreover, we observe SidL-dependent production of 2-AMP-3-phosphoglycerate in macrophages during L. pneumophila infection, the timing of which is consistent with a role for SidL in the early stages of the infection cycle. Thus, our study uncovers a mechanism by which an intracellular pathogen uses the chemical modification of a glycolytic intermediate to target central carbon metabolism in the host.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3240-3257.e16"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13431035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SMD2 reads pseudouridines to regulate mRNA splicing and promote tumorigenesis. SMD2读取假尿嘧啶，调节mRNA剪接，促进肿瘤发生。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-07-15 DOI: 10.1016/j.molcel.2026.06.033

Wei-Ying Meng, Moping Xu, Shu-Xia Sun, Zhi-Yan Sun, Fan-Chen Wang, Yao Lu, Yangchan Li, Jiejun Shi, Jian-Huang Xue

引用次数: 0