Pub Date : 2024-10-03DOI: 10.1016/j.molcel.2024.09.007
Jimmy K. Guo, Mario R. Blanco, Mitchell Guttman
Many reported PRC2-RNA interactions have been shown to be functionally dispensable, raising questions about whether they occur in vivo. Here, we lay out technical issues with existing evidence for direct binding and argue that there is currently a lack of biochemical or functional evidence for direct PRC2-RNA binding in vivo.
{"title":"PRC2-RNA interactions: Viewpoint from Jimmy K. Guo, Mario R. Blanco, and Mitchell Guttman","authors":"Jimmy K. Guo, Mario R. Blanco, Mitchell Guttman","doi":"10.1016/j.molcel.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.007","url":null,"abstract":"Many reported PRC2-RNA interactions have been shown to be functionally dispensable, raising questions about whether they occur <em>in vivo</em>. Here, we lay out technical issues with existing evidence for direct binding and argue that there is currently a lack of biochemical or functional evidence for direct PRC2-RNA binding <em>in vivo</em>.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369138","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}
Pub Date : 2024-10-03DOI: 10.1016/j.molcel.2024.08.028
Johanna Franziska Seidler, Katja Sträßer
Nuclear messenger RNA (mRNA) export is vital for cell survival under both physiological and stress conditions. To cope with stress, cells block bulk mRNA export while selectively exporting stress-specific mRNAs. Under physiological conditions, nuclear adaptor proteins recruit the mRNA exporter to the mRNA for export. By contrast, during stress conditions, the mRNA exporter is likely directly recruited to stress-specific mRNAs at their transcription sites to facilitate selective mRNA export. In this review, we summarize our current understanding of nuclear mRNA export. Importantly, we explore insights into the mechanisms that block bulk mRNA export and facilitate transcript-specific mRNA export under stress, highlighting the gaps that still need to be filled.
{"title":"Understanding nuclear mRNA export: Survival under stress","authors":"Johanna Franziska Seidler, Katja Sträßer","doi":"10.1016/j.molcel.2024.08.028","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.028","url":null,"abstract":"Nuclear messenger RNA (mRNA) export is vital for cell survival under both physiological and stress conditions. To cope with stress, cells block bulk mRNA export while selectively exporting stress-specific mRNAs. Under physiological conditions, nuclear adaptor proteins recruit the mRNA exporter to the mRNA for export. By contrast, during stress conditions, the mRNA exporter is likely directly recruited to stress-specific mRNAs at their transcription sites to facilitate selective mRNA export. In this review, we summarize our current understanding of nuclear mRNA export. Importantly, we explore insights into the mechanisms that block bulk mRNA export and facilitate transcript-specific mRNA export under stress, highlighting the gaps that still need to be filled.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369146","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}
Pub Date : 2024-10-03DOI: 10.1016/j.molcel.2024.09.003
Blerta Xhemalçe, Kyle M. Miller, Natalia Gromak
Complex pathways involving the DNA damage response (DDR) contend with cell-intrinsic and -extrinsic sources of DNA damage. DDR mis-regulation results in genome instability that can contribute to aging and diseases including cancer and neurodegeneration. Recent studies have highlighted key roles for several RNA species in the DDR, including short RNAs and RNA/DNA hybrids (R-loops) at DNA break sites, all contributing to efficient DNA repair. RNAs can undergo more than 170 distinct chemical modifications. These RNA modifications have emerged as key orchestrators of the DDR. Here, we highlight the function of enzyme- and non-enzyme-induced RNA modifications in the DDR, with particular emphasis on m6A, m5C, and RNA editing. We also discuss stress-induced RNA damage, including RNA alkylation/oxidation, RNA-protein crosslinks, and UV-induced RNA damage. Uncovering molecular mechanisms that underpin the contribution of RNA modifications to DDR and genome stability will have direct application to disease and approaches for therapeutic intervention.
{"title":"Epitranscriptome in action: RNA modifications in the DNA damage response","authors":"Blerta Xhemalçe, Kyle M. Miller, Natalia Gromak","doi":"10.1016/j.molcel.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.003","url":null,"abstract":"Complex pathways involving the DNA damage response (DDR) contend with cell-intrinsic and -extrinsic sources of DNA damage. DDR mis-regulation results in genome instability that can contribute to aging and diseases including cancer and neurodegeneration. Recent studies have highlighted key roles for several RNA species in the DDR, including short RNAs and RNA/DNA hybrids (R-loops) at DNA break sites, all contributing to efficient DNA repair. RNAs can undergo more than 170 distinct chemical modifications. These RNA modifications have emerged as key orchestrators of the DDR. Here, we highlight the function of enzyme- and non-enzyme-induced RNA modifications in the DDR, with particular emphasis on m<sup>6</sup>A, m<sup>5</sup>C, and RNA editing. We also discuss stress-induced RNA damage, including RNA alkylation/oxidation, RNA-protein crosslinks, and UV-induced RNA damage. Uncovering molecular mechanisms that underpin the contribution of RNA modifications to DDR and genome stability will have direct application to disease and approaches for therapeutic intervention.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369142","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}
Pub Date : 2024-10-03DOI: 10.1016/j.molcel.2024.09.017
Bryan T. Harada
No Abstract
无摘要
{"title":"The many faces of RNA","authors":"Bryan T. Harada","doi":"10.1016/j.molcel.2024.09.017","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.017","url":null,"abstract":"No Abstract","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369133","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}
Pub Date : 2024-10-03DOI: 10.1016/j.molcel.2024.08.020
Chu-Xiao Liu, Li Yang, Ling-Ling Chen
Circular RNA is a group of covalently closed, single-stranded transcripts with unique biogenesis, stability, and conformation that play distinct roles in modulating cellular functions and also possess a great potential for developing circular RNA-based therapies. Importantly, due to its circular conformation, circular RNA generates distinct intramolecular base pairing that is different from the linear transcript. In this perspective, we review how circular RNA conformation can affect its turnover and modes of action, as well as what factors can modulate circular RNA conformation. We also discuss how understanding circular RNA conformation can facilitate learning about their functions as well as the remaining technological issues to further address their conformation. These efforts will ultimately inform the design of circular RNA-based platforms for biomedical applications.
{"title":"Dynamic conformation: Marching toward circular RNA function and application","authors":"Chu-Xiao Liu, Li Yang, Ling-Ling Chen","doi":"10.1016/j.molcel.2024.08.020","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.020","url":null,"abstract":"Circular RNA is a group of covalently closed, single-stranded transcripts with unique biogenesis, stability, and conformation that play distinct roles in modulating cellular functions and also possess a great potential for developing circular RNA-based therapies. Importantly, due to its circular conformation, circular RNA generates distinct intramolecular base pairing that is different from the linear transcript. In this perspective, we review how circular RNA conformation can affect its turnover and modes of action, as well as what factors can modulate circular RNA conformation. We also discuss how understanding circular RNA conformation can facilitate learning about their functions as well as the remaining technological issues to further address their conformation. These efforts will ultimately inform the design of circular RNA-based platforms for biomedical applications.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369141","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}
Pub Date : 2024-10-03DOI: 10.1016/j.molcel.2024.08.021
Jonathan E. Henninger, Richard A. Young
Foundational models of transcriptional regulation involve the assembly of protein complexes at DNA elements associated with specific genes. These assemblies, which can include transcription factors, cofactors, RNA polymerase, and various chromatin regulators, form dynamic spatial compartments that contribute to both gene regulation and local genome architecture. This DNA-protein-centric view has been modified with recent evidence that RNA molecules have important roles to play in gene regulation and genome structure. Here, we discuss evidence that gene regulation by RNA occurs at multiple levels that include assembly of transcriptional complexes and genome compartments, feedback regulation of active genes, silencing of genes, and control of protein kinases. We thus provide an RNA-centric view of transcriptional regulation that must reside alongside the more traditional DNA-protein-centric perspectives on gene regulation and genome architecture.
转录调控的基本模式涉及在与特定基因相关的 DNA 元件上组装蛋白质复合物。这些集合体可能包括转录因子、辅助因子、RNA 聚合酶和各种染色质调节因子，它们形成了动态的空间分区，有助于基因调控和局部基因组结构。最近有证据表明，RNA 分子在基因调控和基因组结构中发挥着重要作用，从而改变了这种以 DNA 蛋白为中心的观点。在这里，我们讨论了 RNA 在多个水平上进行基因调控的证据，这些水平包括转录复合物和基因组分区的组装、活性基因的反馈调控、基因沉默以及蛋白激酶的控制。因此，我们提供了一种以 RNA 为中心的转录调控观点，它必须与更传统的以 DNA 蛋白为中心的基因调控和基因组结构观点并存。
{"title":"An RNA-centric view of transcription and genome organization","authors":"Jonathan E. Henninger, Richard A. Young","doi":"10.1016/j.molcel.2024.08.021","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.021","url":null,"abstract":"Foundational models of transcriptional regulation involve the assembly of protein complexes at DNA elements associated with specific genes. These assemblies, which can include transcription factors, cofactors, RNA polymerase, and various chromatin regulators, form dynamic spatial compartments that contribute to both gene regulation and local genome architecture. This DNA-protein-centric view has been modified with recent evidence that RNA molecules have important roles to play in gene regulation and genome structure. Here, we discuss evidence that gene regulation by RNA occurs at multiple levels that include assembly of transcriptional complexes and genome compartments, feedback regulation of active genes, silencing of genes, and control of protein kinases. We thus provide an RNA-centric view of transcriptional regulation that must reside alongside the more traditional DNA-protein-centric perspectives on gene regulation and genome architecture.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369143","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}
Pub Date : 2024-10-02DOI: 10.1016/j.molcel.2024.09.002
Dalia Smalakyte, Audrone Ruksenaite, Giedrius Sasnauskas, Giedre Tamulaitiene, Gintautas Tamulaitis
To combat phage infection, type III CRISPR-Cas systems utilize cyclic oligoadenylates (cAn) signaling to activate various auxiliary effectors, including the CRISPR-associated Lon-SAVED protease CalpL, which forms a tripartite effector system together with an anti-σ factor, CalpT, and an ECF-like σ factor, CalpS. Here, we report the characterization of the Candidatus Cloacimonas acidaminovorans CalpL-CalpT-CalpS. We demonstrate that cA4 binding triggers CalpL filament formation and activates it to cleave CalpT within the CalpT-CalpS dimer. This cleavage exposes the CalpT C-degron, which targets it for further degradation by cellular proteases. Consequently, CalpS is released to bind to RNA polymerase, causing growth arrest in E. coli. Furthermore, the CalpL-CalpT-CalpS system is regulated by the SAVED domain of CalpL, which is a ring nuclease that cleaves cA4 in a sequential three-step mechanism. These findings provide key mechanistic details for the activation, proteolytic events, and regulation of the signaling cascade in the type III CRISPR-Cas immunity.
{"title":"Filament formation activates protease and ring nuclease activities of CRISPR Lon-SAVED","authors":"Dalia Smalakyte, Audrone Ruksenaite, Giedrius Sasnauskas, Giedre Tamulaitiene, Gintautas Tamulaitis","doi":"10.1016/j.molcel.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.002","url":null,"abstract":"To combat phage infection, type III CRISPR-Cas systems utilize cyclic oligoadenylates (cA<sub>n</sub>) signaling to activate various auxiliary effectors, including the CRISPR-associated Lon-SAVED protease CalpL, which forms a tripartite effector system together with an anti-σ factor, CalpT, and an ECF-like σ factor, CalpS. Here, we report the characterization of the <em>Candidatus</em> Cloacimonas acidaminovorans CalpL-CalpT-CalpS. We demonstrate that cA<sub>4</sub> binding triggers CalpL filament formation and activates it to cleave CalpT within the CalpT-CalpS dimer. This cleavage exposes the CalpT C-degron, which targets it for further degradation by cellular proteases. Consequently, CalpS is released to bind to RNA polymerase, causing growth arrest in <em>E. coli</em>. Furthermore, the CalpL-CalpT-CalpS system is regulated by the SAVED domain of CalpL, which is a ring nuclease that cleaves cA<sub>4</sub> in a sequential three-step mechanism. These findings provide key mechanistic details for the activation, proteolytic events, and regulation of the signaling cascade in the type III CRISPR-Cas immunity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363100","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}
Pub Date : 2024-10-01DOI: 10.1016/j.molcel.2024.09.004
James M. Bradley, Michael Bunsick, George Ly, Bruno Aquino, Flora Zhiqi Wang, Duncan Holbrook-Smith, Shingo Suginoo, Dylan Bradizza, Naoki Kato, Omar As’sadiq, Nina Marsh, Hiroyuki Osada, François-Didier Boyer, Christopher S.P. McErlean, Yuichiro Tsuchiya, Rajagopal Subramaniam, Dario Bonetta, Peter McCourt, Shelley Lumba
Inter-kingdom communication through small molecules is essential to the coexistence of organisms in an ecosystem. In soil communities, the plant root is a nexus of interactions for a remarkable number of fungi and is a source of small-molecule plant hormones that shape fungal compositions. Although hormone signaling pathways are established in plants, how fungi perceive and respond to molecules is unclear because many plant-associated fungi are recalcitrant to experimentation. Here, we develop an approach using the model fungus, Saccharomyces cerevisiae, to elucidate mechanisms of fungal response to plant hormones. Two plant hormones, strigolactone and methyl jasmonate, produce unique transcript profiles in yeast, affecting phosphate and sugar metabolism, respectively. Genetic analysis in combination with structural studies suggests that SLs require the high-affinity transporter Pho84 to modulate phosphate homeostasis. The ability to study small-molecule plant hormones in a tractable genetic system should have utility in understanding fungal-plant interactions.
{"title":"Modulation of fungal phosphate homeostasis by the plant hormone strigolactone","authors":"James M. Bradley, Michael Bunsick, George Ly, Bruno Aquino, Flora Zhiqi Wang, Duncan Holbrook-Smith, Shingo Suginoo, Dylan Bradizza, Naoki Kato, Omar As’sadiq, Nina Marsh, Hiroyuki Osada, François-Didier Boyer, Christopher S.P. McErlean, Yuichiro Tsuchiya, Rajagopal Subramaniam, Dario Bonetta, Peter McCourt, Shelley Lumba","doi":"10.1016/j.molcel.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.004","url":null,"abstract":"Inter-kingdom communication through small molecules is essential to the coexistence of organisms in an ecosystem. In soil communities, the plant root is a nexus of interactions for a remarkable number of fungi and is a source of small-molecule plant hormones that shape fungal compositions. Although hormone signaling pathways are established in plants, how fungi perceive and respond to molecules is unclear because many plant-associated fungi are recalcitrant to experimentation. Here, we develop an approach using the model fungus, <em>Saccharomyces cerevisiae</em>, to elucidate mechanisms of fungal response to plant hormones. Two plant hormones, strigolactone and methyl jasmonate, produce unique transcript profiles in yeast, affecting phosphate and sugar metabolism, respectively. Genetic analysis in combination with structural studies suggests that SLs require the high-affinity transporter Pho84 to modulate phosphate homeostasis. The ability to study small-molecule plant hormones in a tractable genetic system should have utility in understanding fungal-plant interactions.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360654","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}
Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanistically, H₂S persulfidates the 195th cysteine on S-adenosyl homocysteine hydrolase (SAHH), reducing its enzymatic activity. This leads to decreased homocysteine levels, subsequently lowering cysteine and glutathione concentrations under cystine depletion conditions. These changes ultimately increase the vulnerability of NSCLC cells to ferroptosis. Our findings establish H₂S as a key regulator of homocysteine metabolism and a critical factor in determining NSCLC cell susceptibility to ferroptosis. These results highlight the potential of H₂S-based therapies to improve the efficacy of ferroptosis-targeted cancer treatments for NSCLC.
{"title":"Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer","authors":"Hualei Zheng, Huidi Chen, Yunjie Cai, Min Shen, Xilin Li, Yi Han, Xusheng Deng, Hongjie Cao, Junjia Liu, Hao Li, Benchao Liu, Ganlin Li, Xindong Wang, Hui Chen, Jingjing Hou, Shu-Hai Lin, Lili Zong, Yongyou Zhang","doi":"10.1016/j.molcel.2024.08.035","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.08.035","url":null,"abstract":"Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanistically, H₂S persulfidates the 195<sup>th</sup> cysteine on S-adenosyl homocysteine hydrolase (SAHH), reducing its enzymatic activity. This leads to decreased homocysteine levels, subsequently lowering cysteine and glutathione concentrations under cystine depletion conditions. These changes ultimately increase the vulnerability of NSCLC cells to ferroptosis. Our findings establish H₂S as a key regulator of homocysteine metabolism and a critical factor in determining NSCLC cell susceptibility to ferroptosis. These results highlight the potential of H₂S-based therapies to improve the efficacy of ferroptosis-targeted cancer treatments for NSCLC.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313557","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}
Pub Date : 2024-09-24DOI: 10.1016/j.molcel.2024.09.001
Ti-Chun Chao, Shin-Fu Chen, Hee Jong Kim, Hui-Chi Tang, Hsiang-Ching Tseng, An Xu, Leon Palao, Subash Khadka, Tao Li, Mo-Fan Huang, Dung-Fang Lee, Kenji Murakami, Thomas G. Boyer, Kuang-Lei Tsai
The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the MED13 IDR obstructs the recruitment of RNA Pol II/MED26 onto cMED by direct occlusion of their respective binding sites, leading to functional repression of cMED-dependent transcription. Combined with biochemical and functional analyses, these structures provide a conserved mechanistic framework to explain the basis for CKM-mediated repression of cMED function.
{"title":"Structural basis of the human transcriptional Mediator regulated by its dissociable kinase module","authors":"Ti-Chun Chao, Shin-Fu Chen, Hee Jong Kim, Hui-Chi Tang, Hsiang-Ching Tseng, An Xu, Leon Palao, Subash Khadka, Tao Li, Mo-Fan Huang, Dung-Fang Lee, Kenji Murakami, Thomas G. Boyer, Kuang-Lei Tsai","doi":"10.1016/j.molcel.2024.09.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.001","url":null,"abstract":"The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the MED13 IDR obstructs the recruitment of RNA Pol II/MED26 onto cMED by direct occlusion of their respective binding sites, leading to functional repression of cMED-dependent transcription. Combined with biochemical and functional analyses, these structures provide a conserved mechanistic framework to explain the basis for CKM-mediated repression of cMED function.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317258","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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