Molecular CellPub Date : 2024-11-18DOI: 10.1016/j.molcel.2024.10.026
Yuanlin Xu, Carl A. Morrow, Yassine Laksir, Orla M. Holt, Kezia Taylor, Costas Tsiappourdhi, Patrick Collins, Su Jia, Christos Andreadis, Matthew C. Whitby
{"title":"DNA nicks in both leading and lagging strand templates can trigger break-induced replication","authors":"Yuanlin Xu, Carl A. Morrow, Yassine Laksir, Orla M. Holt, Kezia Taylor, Costas Tsiappourdhi, Patrick Collins, Su Jia, Christos Andreadis, Matthew C. Whitby","doi":"10.1016/j.molcel.2024.10.026","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.026","url":null,"abstract":"Encounters between replication forks and unrepaired DNA single-strand breaks (SSBs) can generate both single-ended and double-ended double-strand breaks (seDSBs and deDSBs). seDSBs can be repaired by break-induced replication (BIR), which is a highly mutagenic pathway that is thought to be responsible for many of the mutations and genome rearrangements that drive cancer development. However, the frequency of BIR’s deployment and its ability to be triggered by both leading and lagging template strand SSBs were unclear. Using site- and strand-specific SSBs generated by nicking enzymes, including CRISPR-Cas9 nickase (Cas9n), we demonstrate that leading and lagging template strand SSBs in fission yeast are typically converted into deDSBs that are repaired by homologous recombination. However, both types of SSBs can also trigger BIR, and the frequency of these events increases when fork convergence is delayed and the non-homologous end joining protein Ku70 is deleted.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"248 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665490","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}
{"title":"PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly.","authors":"Ming-Chieh Chou, Yi-Hsuan Wang, Fei-Yun Chen, Chun-Ying Kung, Kuen-Phon Wu, Jean-Cheng Kuo, Shu-Jou Chan, Mei-Ling Cheng, Chih-Yu Lin, Yu-Chi Chou, Meng-Chiao Ho, Steven Firestine, Jie-Rong Huang, Ruey-Hwa Chen","doi":"10.1016/j.molcel.2023.09.028","DOIUrl":"10.1016/j.molcel.2023.09.028","url":null,"abstract":"<p><p>Purinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. Here, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"4123-4140.e12"},"PeriodicalIF":16.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236987","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}
Molecular CellPub Date : 2023-11-16Epub Date: 2023-10-05DOI: 10.1016/j.molcel.2023.09.016
Bernhard Kuhle, Qi Chen, Paul Schimmel
{"title":"tRNA renovatio: Rebirth through fragmentation.","authors":"Bernhard Kuhle, Qi Chen, Paul Schimmel","doi":"10.1016/j.molcel.2023.09.016","DOIUrl":"10.1016/j.molcel.2023.09.016","url":null,"abstract":"<p><p>tRNA function is based on unique structures that enable mRNA decoding using anticodon trinucleotides. These structures interact with specific aminoacyl-tRNA synthetases and ribosomes using 3D shape and sequence signatures. Beyond translation, tRNAs serve as versatile signaling molecules interacting with other RNAs and proteins. Through evolutionary processes, tRNA fragmentation emerges as not merely random degradation but an act of recreation, generating specific shorter molecules called tRNA-derived small RNAs (tsRNAs). These tsRNAs exploit their linear sequences and newly arranged 3D structures for unexpected biological functions, epitomizing the tRNA \"renovatio\" (from Latin, meaning renewal, renovation, and rebirth). Emerging methods to uncover full tRNA/tsRNA sequences and modifications, combined with techniques to study RNA structures and to integrate AI-powered predictions, will enable comprehensive investigations of tRNA fragmentation products and new interaction potentials in relation to their biological functions. We anticipate that these directions will herald a new era for understanding biological complexity and advancing pharmaceutical engineering.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3953-3971"},"PeriodicalIF":3.784,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41156659","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}
Molecular CellPub Date : 2023-11-16Epub Date: 2023-10-10DOI: 10.1016/j.molcel.2023.09.029
Milos A Cvetkovic, Paolo Passaretti, Agata Butryn, Alicja Reynolds-Winczura, Georgia Kingsley, Aggeliki Skagia, Cyntia Fernandez-Cuesta, Divyasree Poovathumkadavil, Roger George, Anoop S Chauhan, Satpal S Jhujh, Grant S Stewart, Agnieszka Gambus, Alessandro Costa
{"title":"The structural mechanism of dimeric DONSON in replicative helicase activation.","authors":"Milos A Cvetkovic, Paolo Passaretti, Agata Butryn, Alicja Reynolds-Winczura, Georgia Kingsley, Aggeliki Skagia, Cyntia Fernandez-Cuesta, Divyasree Poovathumkadavil, Roger George, Anoop S Chauhan, Satpal S Jhujh, Grant S Stewart, Agnieszka Gambus, Alessandro Costa","doi":"10.1016/j.molcel.2023.09.029","DOIUrl":"10.1016/j.molcel.2023.09.029","url":null,"abstract":"<p><p>The MCM motor of the replicative helicase is loaded onto origin DNA as an inactive double hexamer before replication initiation. Recruitment of activators GINS and Cdc45 upon S-phase transition promotes the assembly of two active CMG helicases. Although work with yeast established the mechanism for origin activation, how CMG is formed in higher eukaryotes is poorly understood. Metazoan Downstream neighbor of Son (DONSON) has recently been shown to deliver GINS to MCM during CMG assembly. What impact this has on the MCM double hexamer is unknown. Here, we used cryoelectron microscopy (cryo-EM) on proteins isolated from replicating Xenopus egg extracts to identify a double CMG complex bridged by a DONSON dimer. We find that tethering elements mediating complex formation are essential for replication. DONSON reconfigures the MCM motors in the double CMG, and primordial dwarfism patients' mutations disrupting DONSON dimerization affect GINS and MCM engagement in human cells and DNA synthesis in Xenopus egg extracts.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"4017-4031.e9"},"PeriodicalIF":14.5,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41205622","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}
Molecular CellPub Date : 2023-11-16Epub Date: 2023-10-24DOI: 10.1016/j.molcel.2023.09.037
Achim Keidel, Alexander Kögel, Peter Reichelt, Eva Kowalinski, Ingmar B Schäfer, Elena Conti
{"title":"Concerted structural rearrangements enable RNA channeling into the cytoplasmic Ski238-Ski7-exosome assembly.","authors":"Achim Keidel, Alexander Kögel, Peter Reichelt, Eva Kowalinski, Ingmar B Schäfer, Elena Conti","doi":"10.1016/j.molcel.2023.09.037","DOIUrl":"10.1016/j.molcel.2023.09.037","url":null,"abstract":"<p><p>The Ski2-Ski3-Ski8 (Ski238) helicase complex directs cytoplasmic mRNAs toward the nucleolytic exosome complex for degradation. In yeast, the interaction between Ski238 and exosome requires the adaptor protein Ski7. We determined different cryo-EM structures of the Ski238 complex depicting the transition from a rigid autoinhibited closed conformation to a flexible active open conformation in which the Ski2 helicase module has detached from the rest of Ski238. The open conformation favors the interaction of the Ski3 subunit with exosome-bound Ski7, leading to the recruitment of the exosome. In the Ski238-Ski7-exosome holocomplex, the Ski2 helicase module binds the exosome cap, enabling the RNA to traverse from the helicase through the internal exosome channel to the Rrp44 exoribonuclease. Our study pinpoints how conformational changes within the Ski238 complex regulate exosome recruitment for RNA degradation. We also reveal the remarkable conservation of helicase-exosome RNA channeling mechanisms throughout eukaryotic nuclear and cytoplasmic exosome complexes.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"4093-4105.e7"},"PeriodicalIF":16.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50162271","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}
Molecular CellPub Date : 2023-11-16Epub Date: 2023-11-06DOI: 10.1016/j.molcel.2023.10.019
Lin He, Chunyu Yu, Sen Qin, Enrun Zheng, Xinhua Liu, Yanhua Liu, Shimiao Yu, Yang Liu, Xuelin Dou, Zesen Shang, Yizhou Wang, Yue Wang, Xuehong Zhou, Boning Liu, Yuping Zhong, Zhiqiang Liu, Jin Lu, Luyang Sun
{"title":"The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity.","authors":"Lin He, Chunyu Yu, Sen Qin, Enrun Zheng, Xinhua Liu, Yanhua Liu, Shimiao Yu, Yang Liu, Xuelin Dou, Zesen Shang, Yizhou Wang, Yue Wang, Xuehong Zhou, Boning Liu, Yuping Zhong, Zhiqiang Liu, Jin Lu, Luyang Sun","doi":"10.1016/j.molcel.2023.10.019","DOIUrl":"10.1016/j.molcel.2023.10.019","url":null,"abstract":"<p><p>While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP component PSMD14 could not be explained by a selective inhibition of proteasomal activity. Here, we report that PSMD14 interacts with NSD2 on chromatin, independent of 19S RP. Functionally, PSMD14 acts as a histone H2AK119 deubiquitinase, facilitating NSD2-directed H3K36 dimethylation. Integrative genomic and epigenomic analyses revealed the functional coordination of PSMD14 and NSD2 in transcriptional activation of target genes (e.g., RELA) linked to myelomagenesis. Reciprocally, RELA transactivates PSMD14, forming a PSMD14/NSD2-RELA positive feedback loop. Remarkably, PSMD14 inhibitors enhance bortezomib sensitivity and fosters anti-myeloma synergy. PSMD14 expression is elevated in myeloma and inversely correlated with overall survival. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of PSMD14 as a therapeutic target to overcome the treatment limitation of myeloma.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"4000-4016.e6"},"PeriodicalIF":16.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71483873","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}
Molecular CellPub Date : 2023-11-16Epub Date: 2023-11-02DOI: 10.1016/j.molcel.2023.10.004
Yuki Aoi, Ali Shilatifard
{"title":"Transcriptional elongation control in developmental gene expression, aging, and disease.","authors":"Yuki Aoi, Ali Shilatifard","doi":"10.1016/j.molcel.2023.10.004","DOIUrl":"10.1016/j.molcel.2023.10.004","url":null,"abstract":"<p><p>The elongation stage of transcription by RNA polymerase II (RNA Pol II) is central to the regulation of gene expression in response to developmental and environmental cues in metazoan. Dysregulated transcriptional elongation has been associated with developmental defects as well as disease and aging processes. Decades of genetic and biochemical studies have painstakingly identified and characterized an ensemble of factors that regulate RNA Pol II elongation. This review summarizes recent findings taking advantage of genetic engineering techniques that probe functions of elongation factors in vivo. We propose a revised model of elongation control in this accelerating field by reconciling contradictory results from the earlier biochemical evidence and the recent in vivo studies. We discuss how elongation factors regulate promoter-proximal RNA Pol II pause release, transcriptional elongation rate and processivity, RNA Pol II stability and RNA processing, and how perturbation of these processes is associated with developmental disorders, neurodegenerative disease, cancer, and aging.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3972-3999"},"PeriodicalIF":16.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71483874","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}
Molecular CellPub Date : 2023-11-10DOI: 10.1016/j.molcel.2023.10.011
Aldwin Suryo Rahmanto, Christian J. Blum, Claudia Scalera, Jan B. Heidelberger, Mikhail Mesitov, Daniel Horn-Ghetko, Justus F. Gräf, Ivan Mikicic, Rebecca Hobrecht, Anna Orekhova, Matthias Ostermaier, Stefanie Ebersberger, Martin M. Möckel, Nils Krapoth, Nádia Da Silva Fernandes, Athanasia Mizi, Yajie Zhu, Jia-Xuan Chen, Chunaram Choudhary, Argyris Papantonis, Petra Beli
{"title":"K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution","authors":"Aldwin Suryo Rahmanto, Christian J. Blum, Claudia Scalera, Jan B. Heidelberger, Mikhail Mesitov, Daniel Horn-Ghetko, Justus F. Gräf, Ivan Mikicic, Rebecca Hobrecht, Anna Orekhova, Matthias Ostermaier, Stefanie Ebersberger, Martin M. Möckel, Nils Krapoth, Nádia Da Silva Fernandes, Athanasia Mizi, Yajie Zhu, Jia-Xuan Chen, Chunaram Choudhary, Argyris Papantonis, Petra Beli","doi":"10.1016/j.molcel.2023.10.011","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.10.011","url":null,"abstract":"<p>Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and they accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA-protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA (mRNA) are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-between-RING (RBR) E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and they suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"2 21","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72365148","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}
Molecular CellPub Date : 2023-11-10DOI: 10.1016/j.molcel.2023.10.012
Shubo Zhao, Jacqueline Cordes, Karolina M. Caban, Maximilian J. Götz, Timur Mackens-Kiani, Anthony J. Veltri, Niladri K. Sinha, Pedro Weickert, Selay Kaya, Graeme Hewitt, Danny D. Nedialkova, Thomas Fröhlich, Roland Beckmann, Allen R. Buskirk, Rachel Green, Julian Stingele
{"title":"RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks","authors":"Shubo Zhao, Jacqueline Cordes, Karolina M. Caban, Maximilian J. Götz, Timur Mackens-Kiani, Anthony J. Veltri, Niladri K. Sinha, Pedro Weickert, Selay Kaya, Graeme Hewitt, Danny D. Nedialkova, Thomas Fröhlich, Roland Beckmann, Allen R. Buskirk, Rachel Green, Julian Stingele","doi":"10.1016/j.molcel.2023.10.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.10.012","url":null,"abstract":"<p>Reactive aldehydes are abundant endogenous metabolites that challenge homeostasis by crosslinking cellular macromolecules. Aldehyde-induced DNA damage requires repair to prevent cancer and premature aging, but it is unknown whether cells also possess mechanisms that resolve aldehyde-induced RNA lesions. Here, we establish photoactivatable ribonucleoside-enhanced crosslinking (PAR-CL) as a model system to study RNA crosslinking damage in the absence of confounding DNA damage in human cells. We find that such RNA damage causes translation stress by stalling elongating ribosomes, which leads to collisions with trailing ribosomes and activation of multiple stress response pathways. Moreover, we discovered a translation-coupled quality control mechanism that resolves covalent RNA-protein crosslinks. Collisions between translating ribosomes and crosslinked mRNA-binding proteins trigger their modification with atypical K6- and K48-linked ubiquitin chains. Ubiquitylation requires the E3 ligase RNF14 and leads to proteasomal degradation of the protein adduct. Our findings identify RNA lesion-induced translational stress as a central component of crosslinking damage.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"61 16","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72364913","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}
{"title":"FMRP phosphorylation modulates neuronal translation through YTHDF1","authors":"Zhongyu Zou, Jiangbo Wei, Yantao Chen, Yunhee Kang, Hailing Shi, Fan Yang, Zhuoyue Shi, Shijie Chen, Ying Zhou, Caraline Sepich-Poore, Xiaoxi Zhuang, Xiaoming Zhou, Hualiang Jiang, Zhexing Wen, Peng Jin, Cheng Luo, Chuan He","doi":"10.1016/j.molcel.2023.10.028","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.10.028","url":null,"abstract":"<p>RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1 for translation upregulation. We show that a new small molecule inhibitor of YTHDF1 can reverse fragile X syndrome (FXS) developmental defects associated with FMRP deficiency in an organoid model. Our study thus reveals that FMRP and its phosphorylation are important regulators of activity-dependent translation during neuronal development and stimulation and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"67 34","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71524863","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}
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