Molecular Cell最新文献_第3页

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

Molecular Cell Pub Date : 2024-11-07 DOI: 10.1016/j.molcel.2024.10.014

Shinichiro Akichika, Tsutomu Suzuki

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

Molecular Cell 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

{"title":"A functional connection between the Microprocessor and a variant NEXT complex","authors":"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","doi":"10.1016/j.molcel.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.015","url":null,"abstract":"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.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"167 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594591","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

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

Molecular Cell Pub Date : 2024-11-07 DOI: 10.1016/j.molcel.2024.10.018

Shane M. Harding

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

Molecular Cell 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

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

Molecular Cell 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

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

Molecular Cell 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

{"title":"Redundant pathways for removal of defective RNA polymerase II complexes at a promoter-proximal pause checkpoint","authors":"Daniel Blears, Jiangman Lou, Nova Fong, Richard Mitter, Ryan M. Sheridan, Dandan He, A. Barbara Dirac-Svejstrup, David Bentley, Jesper Q. Svejstrup","doi":"10.1016/j.molcel.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.012","url":null,"abstract":"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.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"13 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580406","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

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

Molecular Cell 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

{"title":"Threonine-rich carboxyl-terminal extension drives aggregation of stalled polypeptides","authors":"Weili Denyse Chang, Mi-Jeong Yoon, Kian Hua Yeo, Young-Jun Choe","doi":"10.1016/j.molcel.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.011","url":null,"abstract":"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.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"32 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562140","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

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

Molecular Cell 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

{"title":"Spatial organization of PI3K-PI(3,4,5)P3-AKT signaling by focal adhesions","authors":"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","doi":"10.1016/j.molcel.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.010","url":null,"abstract":"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.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"31 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562139","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

mTORC1 activity licenses its own release from the lysosomal surface mTORC1 的活性允许自己从溶酶体表面释放出来

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-31 DOI: 10.1016/j.molcel.2024.10.008

Aishwarya Acharya, Constantinos Demetriades

引用次数: 0

mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes mTORC1 通过自动调节 TFE3 在溶酶体上的存在来限制其活性

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-31 DOI: 10.1016/j.molcel.2024.10.009

Susan Zwakenberg, Denise Westland, Robert M. van Es, Holger Rehmann, Jasper Anink, Jolita Ciapaite, Marjolein Bosma, Ellen Stelloo, Nalan Liv, Paula Sobrevals Alcaraz, Nanda M. Verhoeven-Duif, Judith J.M. Jans, Harmjan R. Vos, Eleonora Aronica, Fried J.T. Zwartkruis

{"title":"mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes","authors":"Susan Zwakenberg, Denise Westland, Robert M. van Es, Holger Rehmann, Jasper Anink, Jolita Ciapaite, Marjolein Bosma, Ellen Stelloo, Nalan Liv, Paula Sobrevals Alcaraz, Nanda M. Verhoeven-Duif, Judith J.M. Jans, Harmjan R. Vos, Eleonora Aronica, Fried J.T. Zwartkruis","doi":"10.1016/j.molcel.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.009","url":null,"abstract":"To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC).","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"533 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556308","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