Molecular Cell最新文献_第9页

Dual modes of ZFC3H1 confer selectivity in nuclear RNA sorting ZFC3H1的双重模式赋予核RNA分拣选择性

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-25 DOI: 10.1016/j.molcel.2024.09.032

Jing Fan, Yimin Wang, Miaomiao Wen, Deng Tong, Kai Wu, Kunming Yan, Peixuan Jia, Yi Zhu, Qinyu Liu, Hecun Zou, Peng Zhao, Falong Lu, Caihong Yun, Yuanchao Xue, Yu Zhou, Hong Cheng

{"title":"Dual modes of ZFC3H1 confer selectivity in nuclear RNA sorting","authors":"Jing Fan, Yimin Wang, Miaomiao Wen, Deng Tong, Kai Wu, Kunming Yan, Peixuan Jia, Yi Zhu, Qinyu Liu, Hecun Zou, Peng Zhao, Falong Lu, Caihong Yun, Yuanchao Xue, Yu Zhou, Hong Cheng","doi":"10.1016/j.molcel.2024.09.032","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.032","url":null,"abstract":"The export and degradation pathways compete to sort nuclear RNAs, yet the default pathway remains unclear. Sorting of mature RNAs to degradation, facilitated by the exosome co-factor poly(A) exosome targeting (PAXT), is particularly challenging for their resemblance to mRNAs intended for translation. Here, we unveil that ZFC3H1, a core PAXT component, is co-transcriptionally loaded onto the first exon/intron of RNA precursors (pre-RNAs). Interestingly, this initial loading does not lead to pre-RNA degradation, as ZFC3H1 adopts a “closed” conformation, effectively blocking exosome recruitment. As processing progresses, RNA fate can be reshaped. Longer RNAs with more exons are allowed for nuclear export. By contrast, short RNAs with fewer exons preferentially recruit transient PAXT components ZC3H3 and RBM26/27 to the 3′ end, triggering ZFC3H1 “opening” and subsequent exosomal degradation. Together, the decoupled loading and activation of ZFC3H1 pre-configures RNA fate for decay while still allowing a switch to nuclear export, depending on mature RNA features.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"97 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489627","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

ZC3H14 facilitates backsplicing by binding to exon-intron boundary and 3′ UTR ZC3H14 通过与外显子-内含子边界和 3′ UTR 结合促进反拼接

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-25 DOI: 10.1016/j.molcel.2024.10.001

Qiqi Li, Gang Yang, Bingbing Ren, Xu Liu, Li-Qin Tang, Qinghua Shi, Ge Shan, Xiaolin Wang

{"title":"ZC3H14 facilitates backsplicing by binding to exon-intron boundary and 3′ UTR","authors":"Qiqi Li, Gang Yang, Bingbing Ren, Xu Liu, Li-Qin Tang, Qinghua Shi, Ge Shan, Xiaolin Wang","doi":"10.1016/j.molcel.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.001","url":null,"abstract":"Circular RNAs (circRNAs) are natural outputs of eukaryotic transcription and RNA processing and have emerged as critical regulators in physiology and diseases. Although multiple cis-elements and trans-factors are reported to modulate the backsplicing of circRNA biogenesis, most of these regulations play roles in flanking introns of circRNAs. Here, using a genome-wide CRISPR knockout screen, we have identified an evolutionarily conserved RNA-binding protein ZC3H14 in regulating circRNA biogenesis. ZC3H14 binds to 3′ and 5′ exon-intron boundaries and 3′ UTRs of cognate mRNAs to promote circRNA biogenesis through dimerization and the association with spliceosome. Yeast knockout of the ZC3H14 ortholog Nab2 has significantly lower levels of circRNAs. Zc3h14−/− mice exhibit disrupted spermatogenesis and reduced testicular circRNA levels. Additionally, expression levels of human ZC3H14 are associated with non-obstructive azoospermia. Our findings reveal a conserved requirement for ZC3H14 in the modulation of backsplicing and link ZC3H14 and circRNA biogenesis to male fertility.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"42 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489587","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

Phosphorylation by JNK switches BRD4 functions JNK 磷酸化改变了 BRD4 的功能

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-24 DOI: 10.1016/j.molcel.2024.09.030

Ballachanda N. Devaiah, Amit Kumar Singh, Jie Mu, Qingrong Chen, Daoud Meerzaman, Dinah S. Singer

{"title":"Phosphorylation by JNK switches BRD4 functions","authors":"Ballachanda N. Devaiah, Amit Kumar Singh, Jie Mu, Qingrong Chen, Daoud Meerzaman, Dinah S. Singer","doi":"10.1016/j.molcel.2024.09.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.030","url":null,"abstract":"Bromodomain 4 (BRD4), a key regulator with pleiotropic functions, plays crucial roles in cancers and cellular stress responses. It exhibits dual functionality: chromatin-bound BRD4 regulates remodeling through its histone acetyltransferase (HAT) activity, while promoter-associated BRD4 regulates transcription through its kinase activity. Notably, chromatin-bound BRD4 lacks kinase activity, and RNA polymerase II (RNA Pol II)-bound BRD4 exhibits no HAT activity. This study unveils one mechanism underlying BRD4’s functional switch. In response to diverse stimuli, c-Jun N-terminal kinase (JNK)-mediated phosphorylation of human BRD4 at Thr1186 and Thr1212 triggers its transient release from chromatin, disrupting its HAT activity and potentiating its kinase activity. Released BRD4 directly interacts with and phosphorylates RNA Pol II, PTEFb, and c-Myc, thereby promoting transcription of target genes involved in immune and inflammatory responses. JNK-mediated BRD4 functional switching induces CD8 expression in thymocytes and epithelial-to-mesenchymal transition (EMT) in prostate cancer cells. These findings elucidate the mechanism by which BRD4 transitions from a chromatin regulator to a transcriptional activator.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"109 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489217","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

Hydrogen sulfide: A whiff of trouble for cancer cell survival 硫化氢癌细胞生存的一缕曙光

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-17 DOI: 10.1016/j.molcel.2024.09.027

Jung Seung Nam, Maya S. Dixon, Iok In Christine Chio

引用次数: 0

Where to start? Activity-dependent alternative translation initiation generates multifunctional proteoforms in the brain 从哪里开始？活动依赖性替代翻译起始在大脑中产生多功能蛋白形式

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-17 DOI: 10.1016/j.molcel.2024.09.029

Adam Kosti, Gary J. Bassell

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Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma NBR1 和 p62 对肝星状细胞 STING 通路的对立调控决定了肝细胞癌的发展进程

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-17 DOI: 10.1016/j.molcel.2024.09.026

Sadaaki Nishimura, Juan F. Linares, Antoine L’Hermitte, Angeles Duran, Tania Cid-Diaz, Anxo Martinez-Ordoñez, Marc Ruiz-Martinez, Yotaro Kudo, Antonio Marzio, Mathias Heikenwalder, Lewis R. Roberts, Maria T. Diaz-Meco, Jorge Moscat

{"title":"Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma","authors":"Sadaaki Nishimura, Juan F. Linares, Antoine L’Hermitte, Angeles Duran, Tania Cid-Diaz, Anxo Martinez-Ordoñez, Marc Ruiz-Martinez, Yotaro Kudo, Antonio Marzio, Mathias Heikenwalder, Lewis R. Roberts, Maria T. Diaz-Meco, Jorge Moscat","doi":"10.1016/j.molcel.2024.09.026","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.026","url":null,"abstract":"Hepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8+ T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8+ T cell responses to restrain HCC progression.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"7 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444066","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

Crossing the border: Replication fork adducts move to lysosomes for autophagic repair 跨越边界：复制叉加合物进入溶酶体进行自噬修复

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-17 DOI: 10.1016/j.molcel.2024.09.021

Sangin Kim, Roger A. Greenberg

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Stalling out chromatin machinery—Oncohistone mutation disrupts heterochromatin memory 染色质机制停滞不前--Oncohistone 基因突变破坏了异染色质记忆

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-17 DOI: 10.1016/j.molcel.2024.09.028

Sara R. Wasserman, Nathaniel A. Hathaway

引用次数: 0

Transcription dynamics and genome organization in the mammalian nucleus: Recent advances 哺乳动物细胞核中的转录动态和基因组组织：最新进展

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-15 DOI: 10.1016/j.molcel.2024.09.022

Kaustubh Wagh, Diana A. Stavreva, Gordon L. Hager

引用次数: 0

Redirecting the pioneering function of FOXA1 with covalent small molecules 用共价小分子重定向 FOXA1 的先驱功能

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-15 DOI: 10.1016/j.molcel.2024.09.024

Sang Joon Won, Yuxiang Zhang, Christopher J. Reinhardt, Lauren M. Hargis, Nicole S. MacRae, Kristen E. DeMeester, Evert Njomen, Jarrett R. Remsberg, Bruno Melillo, Benjamin F. Cravatt, Michael A. Erb

{"title":"Redirecting the pioneering function of FOXA1 with covalent small molecules","authors":"Sang Joon Won, Yuxiang Zhang, Christopher J. Reinhardt, Lauren M. Hargis, Nicole S. MacRae, Kristen E. DeMeester, Evert Njomen, Jarrett R. Remsberg, Bruno Melillo, Benjamin F. Cravatt, Michael A. Erb","doi":"10.1016/j.molcel.2024.09.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.024","url":null,"abstract":"Pioneer transcription factors (TFs) bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic compounds that stereoselectively and site-specifically bind the pioneer TF forkhead box protein A1 (FOXA1) at a cysteine (C258) within the forkhead DNA-binding domain. We show that these covalent ligands react with FOXA1 in a DNA-dependent manner and rapidly remodel its pioneer activity in prostate cancer cells reflected in redistribution of FOXA1 binding across the genome and directionally correlated changes in chromatin accessibility. Motif analysis supports a mechanism where the ligands relax the canonical DNA-binding preference of FOXA1 by strengthening interactions with suboptimal sequences in predicted proximity to C258. Our findings reveal a striking plasticity underpinning the pioneering function of FOXA1 that can be controlled by small molecules.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"65 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436311","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