Pub Date : 2025-11-03DOI: 10.1038/s41594-025-01696-1
Qiaozhen Ye, Minheng Gong, Jiaxi Cai, Lydia R. Chambers, Huilin Zhou, Raymond T. Suhandynata, Kevin D. Corbett
Ubiquitination is a fundamental eukaryotic protein post-translational modification pathway, in which ubiquitin or a ubiquitin-like protein (Ubl) is typically conjugated to a lysine of a target protein. Ubiquitination is initiated by adenylation of the Ubl C terminus, followed by sequential formation of Ubl–cysteine thioester intermediates with E1, E2 and (optionally) E3 proteins before formation of the final Ubl–lysine isopeptide linkage. Recent work has revealed two ubiquitination-related bacterial pathways in the context of antiphage immunity. Bioinformatics analyses have hinted at the existence of additional uncharacterized bacterial pathways that include ubiquitination-like machinery. Here, we describe the architecture and biochemical mechanisms of an alternative Bub (bacterial ubiquitination-like) pathway, revealing structural parallels and mechanistic differences when compared to other ubiquitination pathways. We show that Bub operons encode functional E1, E2 and Ubl proteins that are related to their eukaryotic counterparts but likely function through oxyester rather than thioester intermediates. We also identify an enzyme family in Bub operons with a conserved catalytic site and a role in Ubl–target conjugation. The genomic context of Bub operons suggests that they also function in antiphage immunity and we present evidence that one Bub pathway may regulate translation in response to stress. Overall, our results reveal an uncharacterized family of bacterial ubiquitination-related pathways with a distinctive biochemical mechanism. Ye et al. define the structure and mechanisms of a bacterial pathway that performs ubiquitination-like protein conjugation, revealing new insights into the evolution and biological roles of ubiquitination pathways across kingdoms.
{"title":"Mechanistic basis for protein conjugation in a diverged bacterial ubiquitination pathway","authors":"Qiaozhen Ye, Minheng Gong, Jiaxi Cai, Lydia R. Chambers, Huilin Zhou, Raymond T. Suhandynata, Kevin D. Corbett","doi":"10.1038/s41594-025-01696-1","DOIUrl":"10.1038/s41594-025-01696-1","url":null,"abstract":"Ubiquitination is a fundamental eukaryotic protein post-translational modification pathway, in which ubiquitin or a ubiquitin-like protein (Ubl) is typically conjugated to a lysine of a target protein. Ubiquitination is initiated by adenylation of the Ubl C terminus, followed by sequential formation of Ubl–cysteine thioester intermediates with E1, E2 and (optionally) E3 proteins before formation of the final Ubl–lysine isopeptide linkage. Recent work has revealed two ubiquitination-related bacterial pathways in the context of antiphage immunity. Bioinformatics analyses have hinted at the existence of additional uncharacterized bacterial pathways that include ubiquitination-like machinery. Here, we describe the architecture and biochemical mechanisms of an alternative Bub (bacterial ubiquitination-like) pathway, revealing structural parallels and mechanistic differences when compared to other ubiquitination pathways. We show that Bub operons encode functional E1, E2 and Ubl proteins that are related to their eukaryotic counterparts but likely function through oxyester rather than thioester intermediates. We also identify an enzyme family in Bub operons with a conserved catalytic site and a role in Ubl–target conjugation. The genomic context of Bub operons suggests that they also function in antiphage immunity and we present evidence that one Bub pathway may regulate translation in response to stress. Overall, our results reveal an uncharacterized family of bacterial ubiquitination-related pathways with a distinctive biochemical mechanism. Ye et al. define the structure and mechanisms of a bacterial pathway that performs ubiquitination-like protein conjugation, revealing new insights into the evolution and biological roles of ubiquitination pathways across kingdoms.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"71-83"},"PeriodicalIF":10.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427704","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 : 2025-10-31DOI: 10.1038/s41594-025-01702-6
Bing Wang, Renee D. Hoffman, Ya-Ming Hou, Hong Li
Retrons have been recently identified as bacterial defense systems that employ a tripartite of reverse transcriptase, non-coding RNA (ncRNA) and its derived multi-copy single stranded DNA (msDNA) to sequester effector activity. Phage invasion activates retrons, triggering effector activity and inducing abortive infection and cell growth arrest. Ec78 differs from other retrons by leveraging the Septu defense system, a stand-alone ATPase–nuclease pair (PtuAB), by reshaping the phage sensing and molecular assembly processes of PtuAB. To elucidate how Ec78 hijacks PtuAB, we determined electron cryomicroscopy structures of Ec78 as well as the retron-displaced PtuAB. We show that the Ec78-associated ATPase, PtuA, acquired unique elements that enable its interactions with the reverse transcriptase and the msDNA, and self-assembly when displaced by the retron. By biochemical and mutational analyses, we also show that the retron-displaced PtuAB forms a tetramer, unlike its stand-alone counterpart, that restricts the host. However, in the presence of the retron, the retron-displaced PtuAB confers a well-controlled immune response, eliciting ATP hydrolysis- and msDNA-regulated targeting to host factors. Our studies reveal an evolutionary principle for retrons to co-opt conserved enzyme modules for defense in response to different cellular needs. Wang et al. combine structural and biochemical analyses to show how a bacterial defense system, Ec78 retron, employs reverse-transcriptase-derived DNA to regulate an ATPase–nuclease pair for phage defense.
{"title":"Structural basis for retron co-option of anti-phage ATPase-nuclease","authors":"Bing Wang, Renee D. Hoffman, Ya-Ming Hou, Hong Li","doi":"10.1038/s41594-025-01702-6","DOIUrl":"10.1038/s41594-025-01702-6","url":null,"abstract":"Retrons have been recently identified as bacterial defense systems that employ a tripartite of reverse transcriptase, non-coding RNA (ncRNA) and its derived multi-copy single stranded DNA (msDNA) to sequester effector activity. Phage invasion activates retrons, triggering effector activity and inducing abortive infection and cell growth arrest. Ec78 differs from other retrons by leveraging the Septu defense system, a stand-alone ATPase–nuclease pair (PtuAB), by reshaping the phage sensing and molecular assembly processes of PtuAB. To elucidate how Ec78 hijacks PtuAB, we determined electron cryomicroscopy structures of Ec78 as well as the retron-displaced PtuAB. We show that the Ec78-associated ATPase, PtuA, acquired unique elements that enable its interactions with the reverse transcriptase and the msDNA, and self-assembly when displaced by the retron. By biochemical and mutational analyses, we also show that the retron-displaced PtuAB forms a tetramer, unlike its stand-alone counterpart, that restricts the host. However, in the presence of the retron, the retron-displaced PtuAB confers a well-controlled immune response, eliciting ATP hydrolysis- and msDNA-regulated targeting to host factors. Our studies reveal an evolutionary principle for retrons to co-opt conserved enzyme modules for defense in response to different cellular needs. Wang et al. combine structural and biochemical analyses to show how a bacterial defense system, Ec78 retron, employs reverse-transcriptase-derived DNA to regulate an ATPase–nuclease pair for phage defense.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"53-62"},"PeriodicalIF":10.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01702-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404951","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}
Pub Date : 2025-10-31DOI: 10.1038/s41594-025-01705-3
Celso M. Teixeira-Duarte, Weizhong Zeng, Youxing Jiang
TRPM4 is a member of the transient receptor potential melastatin channel subfamily and functions as a Ca2+-activated monovalent-selective cation channel. It is widely expressed in various cells and tissues, where its activation depolarizes the plasma membrane potential and modulates various Ca2+-dependent biological processes. TRPM4 activity is potentiated by membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and inhibited by cytosolic free adenosine triphosphate (ATP), allowing the channel to transition between different functional states in response to dynamic changes in cellular Ca2+, ATP and PtdIns(4,5)P2 levels during signaling events. Here we present single-particle cryo-electron microscopy structures of human TRPM4 in four distinct states: apo closed, Ca2+-bound putative desensitized, Ca2+-PtdIns(4,5)P2-bound open and ATP-bound inhibited. Combined with mutagenesis and electrophysiological analyses, these structures reveal the molecular mechanisms underlying TRPM4 activation, desensitization and inhibition. Given the central roles of Ca2+, PtdIns(4,5)P2 and ATP in cellular signaling, this work provides a structural foundation to decipher the physiological functions of TRPM4 across diverse biological systems. Transient receptor potential channel subfamily M member 4 (TRPM4) is a cation channel that modulates various Ca2+-dependent physiological processes. Teixeira-Duarte et al. present human TRPM4 structures in various conformational states, providing insights into channel regulation by Ca2+, PtdIns(4,5)P2 and adenosine triphosphate.
{"title":"Structural landscape of activation, desensitization and inhibition in the human TRPM4 channel","authors":"Celso M. Teixeira-Duarte, Weizhong Zeng, Youxing Jiang","doi":"10.1038/s41594-025-01705-3","DOIUrl":"10.1038/s41594-025-01705-3","url":null,"abstract":"TRPM4 is a member of the transient receptor potential melastatin channel subfamily and functions as a Ca2+-activated monovalent-selective cation channel. It is widely expressed in various cells and tissues, where its activation depolarizes the plasma membrane potential and modulates various Ca2+-dependent biological processes. TRPM4 activity is potentiated by membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and inhibited by cytosolic free adenosine triphosphate (ATP), allowing the channel to transition between different functional states in response to dynamic changes in cellular Ca2+, ATP and PtdIns(4,5)P2 levels during signaling events. Here we present single-particle cryo-electron microscopy structures of human TRPM4 in four distinct states: apo closed, Ca2+-bound putative desensitized, Ca2+-PtdIns(4,5)P2-bound open and ATP-bound inhibited. Combined with mutagenesis and electrophysiological analyses, these structures reveal the molecular mechanisms underlying TRPM4 activation, desensitization and inhibition. Given the central roles of Ca2+, PtdIns(4,5)P2 and ATP in cellular signaling, this work provides a structural foundation to decipher the physiological functions of TRPM4 across diverse biological systems. Transient receptor potential channel subfamily M member 4 (TRPM4) is a cation channel that modulates various Ca2+-dependent physiological processes. Teixeira-Duarte et al. present human TRPM4 structures in various conformational states, providing insights into channel regulation by Ca2+, PtdIns(4,5)P2 and adenosine triphosphate.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"43-52"},"PeriodicalIF":10.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01705-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404899","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}
Pub Date : 2025-10-31DOI: 10.1038/s41594-025-01704-4
Yan Yan, X. Edward Zhou, Stacey L. Thomas, Minmin Liu, Gan-Qiang Lai, Evan J. Worden, Peter A. Jones, Ting-Hai Xu
De novo DNA methylation is mediated by DNA methyltransferases DNMT3A and DNMT3B, in cooperation with the catalytically inactive paralogs DNMT3L and DNMT3B3. DNMT3L is predominantly expressed in embryonic stem cells to establish methylation patterns and is silenced upon differentiation, with DNMT3B3 substituting in somatic cells. Here we present high-resolution cryo-electron microscopy structures of nucleosome-bound, full-length DNMT3A2–3L and its oligomeric assemblies in the nucleosome-free state. We identified the critical role of DNMT3L as a histone modification sensor, guiding chromatin engagement through a mechanism distinct from DNMT3B3. The structures show a 180° rotated ‘switching helix’ in DNMT3L that prevents direct interaction with the nucleosome acidic patch. Instead, nucleosome binding is mediated by the DNMT3L ADD domain, while the DNMT3A PWWP domain exhibits reduced engagement in the absence of H3K36 methylation. The oligomeric arrangement of DNMT3A2–3L in nucleosome-free states highlights its dynamic assembly and potential allosteric regulation. We further capture dynamic structural movements of DNMT3A2–3L on nucleosomes. These findings uncover a previously unknown mechanism by which DNMT3A–3L mediates de novo DNA methylation on chromatin through complex assembly, histone tail sensing, dynamic DNA search and regulated nucleosome engagement, providing insights into epigenetic regulation. Yan et al. use cryo-EM to obtain structures that reveal how DNMT3A2 and DNMT3L cooperate to read histone signals and bind chromatin, illustrating a mechanism that controls DNA methylation and shapes epigenetic regulation.
{"title":"Mechanisms of DNMT3A–3L-mediated de novo DNA methylation on chromatin","authors":"Yan Yan, X. Edward Zhou, Stacey L. Thomas, Minmin Liu, Gan-Qiang Lai, Evan J. Worden, Peter A. Jones, Ting-Hai Xu","doi":"10.1038/s41594-025-01704-4","DOIUrl":"10.1038/s41594-025-01704-4","url":null,"abstract":"De novo DNA methylation is mediated by DNA methyltransferases DNMT3A and DNMT3B, in cooperation with the catalytically inactive paralogs DNMT3L and DNMT3B3. DNMT3L is predominantly expressed in embryonic stem cells to establish methylation patterns and is silenced upon differentiation, with DNMT3B3 substituting in somatic cells. Here we present high-resolution cryo-electron microscopy structures of nucleosome-bound, full-length DNMT3A2–3L and its oligomeric assemblies in the nucleosome-free state. We identified the critical role of DNMT3L as a histone modification sensor, guiding chromatin engagement through a mechanism distinct from DNMT3B3. The structures show a 180° rotated ‘switching helix’ in DNMT3L that prevents direct interaction with the nucleosome acidic patch. Instead, nucleosome binding is mediated by the DNMT3L ADD domain, while the DNMT3A PWWP domain exhibits reduced engagement in the absence of H3K36 methylation. The oligomeric arrangement of DNMT3A2–3L in nucleosome-free states highlights its dynamic assembly and potential allosteric regulation. We further capture dynamic structural movements of DNMT3A2–3L on nucleosomes. These findings uncover a previously unknown mechanism by which DNMT3A–3L mediates de novo DNA methylation on chromatin through complex assembly, histone tail sensing, dynamic DNA search and regulated nucleosome engagement, providing insights into epigenetic regulation. Yan et al. use cryo-EM to obtain structures that reveal how DNMT3A2 and DNMT3L cooperate to read histone signals and bind chromatin, illustrating a mechanism that controls DNA methylation and shapes epigenetic regulation.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"171-183"},"PeriodicalIF":10.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404897","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 : 2025-10-28DOI: 10.1038/s41594-025-01698-z
Francesca Vallese
The structural biology community in New York City combines expertise and access to cutting-edge instrumentation that fosters cooperation. Working collaboratively is indispensable because developing interdisciplinary tools can enable discoveries in cell, structural and molecular biology.
{"title":"New York City’s structural biology mosaic","authors":"Francesca Vallese","doi":"10.1038/s41594-025-01698-z","DOIUrl":"10.1038/s41594-025-01698-z","url":null,"abstract":"The structural biology community in New York City combines expertise and access to cutting-edge instrumentation that fosters cooperation. Working collaboratively is indispensable because developing interdisciplinary tools can enable discoveries in cell, structural and molecular biology.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 11","pages":"2132-2133"},"PeriodicalIF":10.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380918","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 : 2025-10-24DOI: 10.1038/s41594-025-01690-7
Eric M. Smith, Jimmy Ly, Sofia Haug, Iain M. Cheeseman
RNase MRP and RNase P are evolutionarily related complexes that facilitate rRNA and tRNA biogenesis, respectively. The two enzymes share nearly all protein subunits and have evolutionarily related catalytic RNAs. Notably, RNase P includes a unique subunit, RPP21, whereas no RNase MRP-specific proteins have been found in humans, limiting molecular analyses of RNase MRP function. Here, we identify the RNase MRP-specific proteins, C18orf21 (RMP24) and NEPRO (RMP64). C18orf21/RMP24 and RPP21 display significant structural homology, but we identify specific regions that drive interactions with their respective complexes. By targeting these RNase MRP-specific subunits, our functional analysis reveals that RNase MRP is essential for rRNA processing and preferentially required for 40S ribosome biogenesis. Finally, we determine that disease-associated mutations in RMP64 impair its association with RNase MRP subunits. Together, our findings elucidate the molecular determinants of RNase MRP function and underscore its critical role in ribosome biogenesis and disease. The authors identify the human RNase MRP-specific proteins, RMP24 (C18orf21) and RMP64 (Nepro), define their role in 40S ribosome biogenesis, and reveal how disease-linked RMP64 mutations disrupt complex assembly.
{"title":"RNase MRP subunit composition and role in 40S ribosome biogenesis","authors":"Eric M. Smith, Jimmy Ly, Sofia Haug, Iain M. Cheeseman","doi":"10.1038/s41594-025-01690-7","DOIUrl":"10.1038/s41594-025-01690-7","url":null,"abstract":"RNase MRP and RNase P are evolutionarily related complexes that facilitate rRNA and tRNA biogenesis, respectively. The two enzymes share nearly all protein subunits and have evolutionarily related catalytic RNAs. Notably, RNase P includes a unique subunit, RPP21, whereas no RNase MRP-specific proteins have been found in humans, limiting molecular analyses of RNase MRP function. Here, we identify the RNase MRP-specific proteins, C18orf21 (RMP24) and NEPRO (RMP64). C18orf21/RMP24 and RPP21 display significant structural homology, but we identify specific regions that drive interactions with their respective complexes. By targeting these RNase MRP-specific subunits, our functional analysis reveals that RNase MRP is essential for rRNA processing and preferentially required for 40S ribosome biogenesis. Finally, we determine that disease-associated mutations in RMP64 impair its association with RNase MRP subunits. Together, our findings elucidate the molecular determinants of RNase MRP function and underscore its critical role in ribosome biogenesis and disease. The authors identify the human RNase MRP-specific proteins, RMP24 (C18orf21) and RMP64 (Nepro), define their role in 40S ribosome biogenesis, and reveal how disease-linked RMP64 mutations disrupt complex assembly.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"20-33"},"PeriodicalIF":10.1,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01690-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357623","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}
Pub Date : 2025-10-24DOI: 10.1038/s41594-025-01692-5
Sushant Kumar, Fei Jin, Sung Jin Park, Wooyoung Choi, Sarah I. Keuning, Richard P. Massimino, Simon Vu, Wei Lü, Juan Du
Detecting noxious heat is vital for survival, triggering protective pain responses. The TRPM3 channel is a key nociceptor and a promising therapeutic target for pain and neurological disorders. Here we show that the rabbit TRPM3 is intrinsically dynamic, with its intracellular domain (ICD) sampling both resting and activated states, but favoring the resting state in the absence of stimulation. We reveal that heat and the synthetic agonist CIM0216 shift the equilibrium toward activation by inducing a similar ICD rearrangement. Mutations that facilitate ICD movement enhance sensitivity to both thermal and chemical stimuli, underscoring the central role of the ICD in channel gating. We also show that the antagonist primidone binds the same site as CIM0216 in the S1–S4 domain but inhibits channel activation. This study provides a structural framework for a mechanistic understanding of thermal and chemical gating of TRPM3 and for guiding the rational design of TRPM3-targeted analgesics and neurotherapeutics. TRPM3 is an ion channel that helps the body sense heat and contributes to pain. The authors show that both heat and small chemical molecules switch it on through similar changes inside the protein.
{"title":"Structural basis for agonist and heat activation of nociceptor TRPM3","authors":"Sushant Kumar, Fei Jin, Sung Jin Park, Wooyoung Choi, Sarah I. Keuning, Richard P. Massimino, Simon Vu, Wei Lü, Juan Du","doi":"10.1038/s41594-025-01692-5","DOIUrl":"10.1038/s41594-025-01692-5","url":null,"abstract":"Detecting noxious heat is vital for survival, triggering protective pain responses. The TRPM3 channel is a key nociceptor and a promising therapeutic target for pain and neurological disorders. Here we show that the rabbit TRPM3 is intrinsically dynamic, with its intracellular domain (ICD) sampling both resting and activated states, but favoring the resting state in the absence of stimulation. We reveal that heat and the synthetic agonist CIM0216 shift the equilibrium toward activation by inducing a similar ICD rearrangement. Mutations that facilitate ICD movement enhance sensitivity to both thermal and chemical stimuli, underscoring the central role of the ICD in channel gating. We also show that the antagonist primidone binds the same site as CIM0216 in the S1–S4 domain but inhibits channel activation. This study provides a structural framework for a mechanistic understanding of thermal and chemical gating of TRPM3 and for guiding the rational design of TRPM3-targeted analgesics and neurotherapeutics. TRPM3 is an ion channel that helps the body sense heat and contributes to pain. The authors show that both heat and small chemical molecules switch it on through similar changes inside the protein.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"34-42"},"PeriodicalIF":10.1,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01692-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357624","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}
Pub Date : 2025-10-23DOI: 10.1038/s41594-025-01685-4
Rebecca M. Starble, Eric G. Sun, Rana Gbyli, Jonathan Radda, Jiuwei Lu, Tyler B. Jensen, Ning Sun, Nelli Khudaverdyan, Ting Zhao, Bomiao Hu, Mary Ann Melnick, Shuai Zhao, Nitin Roper, Gang Greg Wang, Alan J. Tackett, Yinsheng Wang, Jikui Song, Katerina Politi, Siyuan Wang, Andrew Z. Xiao
In mammalian cells, gene copy number is controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, increasing the copy number and expression of tumor-promoting genes and thus promoting cancer progression. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification is frequent. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the underlying mechanisms are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naive tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identify a global chromatin-priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading and inter-TAD interactions, which occur before the onset of oncogene amplification. Furthermore, we show that METTL7A, reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. METTL7A appears to remodel the chromatin landscape prior to large-scale copy number gains. Although METTL7A depletion exerts little phenotypical effects on drug-naive cells, its depletion prevents the formation and maintenance of TKI resistant-clones, showcasing its role as cells become resistant. In summary, we unveil a mechanism required for the acquisition of TKI resistance regulated by an unexpected chromatin function of METTL7A. Starble, Sun, and colleagues identify an epigenetic priming mechanism that promotes oncogene amplification in acquired resistance to tyrosine kinase inhibitors and establishes a role of METTL7A in this process.
{"title":"Epigenetic priming promotes tyrosine kinase inhibitor resistance and oncogene amplification","authors":"Rebecca M. Starble, Eric G. Sun, Rana Gbyli, Jonathan Radda, Jiuwei Lu, Tyler B. Jensen, Ning Sun, Nelli Khudaverdyan, Ting Zhao, Bomiao Hu, Mary Ann Melnick, Shuai Zhao, Nitin Roper, Gang Greg Wang, Alan J. Tackett, Yinsheng Wang, Jikui Song, Katerina Politi, Siyuan Wang, Andrew Z. Xiao","doi":"10.1038/s41594-025-01685-4","DOIUrl":"10.1038/s41594-025-01685-4","url":null,"abstract":"In mammalian cells, gene copy number is controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, increasing the copy number and expression of tumor-promoting genes and thus promoting cancer progression. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification is frequent. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the underlying mechanisms are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naive tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identify a global chromatin-priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading and inter-TAD interactions, which occur before the onset of oncogene amplification. Furthermore, we show that METTL7A, reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. METTL7A appears to remodel the chromatin landscape prior to large-scale copy number gains. Although METTL7A depletion exerts little phenotypical effects on drug-naive cells, its depletion prevents the formation and maintenance of TKI resistant-clones, showcasing its role as cells become resistant. In summary, we unveil a mechanism required for the acquisition of TKI resistance regulated by an unexpected chromatin function of METTL7A. Starble, Sun, and colleagues identify an epigenetic priming mechanism that promotes oncogene amplification in acquired resistance to tyrosine kinase inhibitors and establishes a role of METTL7A in this process.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"7-19"},"PeriodicalIF":10.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01685-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351656","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}
Pub Date : 2025-10-20DOI: 10.1038/s41594-025-01691-6
Arunkumar Sundaram, Qianru Li, Yu Wan, Josephine Tang, Haoxi Wu, Luka Smalinskaitė, Ramanujan S. Hegde, Zhe Ji, Robert J. Keenan
Protein biogenesis at the endoplasmic reticulum requires translocons comprising the Sec61 protein-conducting channel and several dynamically associated accessory factors. Here we used transcriptome-wide selective ribosome profiling in human cells to monitor cotranslational interactions of accessory factors for N-glycosylation (the OST-A complex) and multipass membrane protein synthesis (the GEL, PAT and BOS complexes). OST-A was preferentially recruited to open Sec61 channels engaged in polypeptide translocation; conversely, GEL, PAT and BOS were recruited synchronously to closed Sec61 channels and stabilized by newly inserted transmembrane domains. Translocon composition changed repeatedly and reversibly during the synthesis of topologically complex multipass membrane proteins. These data establish the molecular logic that underlies substrate-driven translocon remodeling, events that are crucial for the efficient biogenesis of secretory and membrane proteins. The authors use selective ribosome profiling to define how and when factors for N-glycosylation and membrane insertion engage and disengage from the core Sec61 translocation channel during biogenesis of secretory and membrane proteins at the endoplasmic reticulum.
{"title":"Global analysis of translocon remodeling during protein synthesis at the ER","authors":"Arunkumar Sundaram, Qianru Li, Yu Wan, Josephine Tang, Haoxi Wu, Luka Smalinskaitė, Ramanujan S. Hegde, Zhe Ji, Robert J. Keenan","doi":"10.1038/s41594-025-01691-6","DOIUrl":"10.1038/s41594-025-01691-6","url":null,"abstract":"Protein biogenesis at the endoplasmic reticulum requires translocons comprising the Sec61 protein-conducting channel and several dynamically associated accessory factors. Here we used transcriptome-wide selective ribosome profiling in human cells to monitor cotranslational interactions of accessory factors for N-glycosylation (the OST-A complex) and multipass membrane protein synthesis (the GEL, PAT and BOS complexes). OST-A was preferentially recruited to open Sec61 channels engaged in polypeptide translocation; conversely, GEL, PAT and BOS were recruited synchronously to closed Sec61 channels and stabilized by newly inserted transmembrane domains. Translocon composition changed repeatedly and reversibly during the synthesis of topologically complex multipass membrane proteins. These data establish the molecular logic that underlies substrate-driven translocon remodeling, events that are crucial for the efficient biogenesis of secretory and membrane proteins. The authors use selective ribosome profiling to define how and when factors for N-glycosylation and membrane insertion engage and disengage from the core Sec61 translocation channel during biogenesis of secretory and membrane proteins at the endoplasmic reticulum.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2517-2525"},"PeriodicalIF":10.1,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01691-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331585","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}
Pub Date : 2025-10-17DOI: 10.1038/s41594-025-01687-2
Viraat Y. Goel, Nicholas G. Aboreden, James M. Jusuf, Haoyue Zhang, Luisa P. Mori, Leonid A. Mirny, Gerd A. Blobel, Edward J. Banigan, Anders S. Hansen
As cells exit mitosis and enter G1, chromosomes decompact and transcription is reestablished. Hi-C studies have indicated that all interphase three-dimensional genome features, including A/B compartments, topologically associating domains and CCCTC-binding factor loops, are lost during mitosis. However, Hi-C is insensitive to features such as microcompartments, nested focal interactions between cis-regulatory elements. Here we apply region capture Micro-C to mouse erythroblasts from mitosis to G1. We unexpectedly observe microcompartments in prometaphase, which strengthen in anaphase and telophase before weakening throughout G1. Microcompartment anchors coincide with transcriptionally spiking promoters during mitosis. Loss of condensin loop extrusion differentially impacts microcompartments and A/B compartments, suggesting that they are partially distinct. Polymer modeling shows that microcompartment formation is favored by chromatin compaction and disfavored by loop extrusion, providing a basis for strong microcompartmentalization in anaphase and telophase. Our results suggest that compaction and homotypic affinity drive microcompartment formation, which may explain transient transcriptional spiking at mitotic exit. Goel et al. produce high-resolution three-dimensional genome structure mapping from mitosis to G1 phase to show unseen interactions between enhancers and promoters in prometaphase. Polymer modeling indicates the interactions are facilitated by chromosome compaction.
{"title":"Dynamics of microcompartment formation at the mitosis-to-G1 transition","authors":"Viraat Y. Goel, Nicholas G. Aboreden, James M. Jusuf, Haoyue Zhang, Luisa P. Mori, Leonid A. Mirny, Gerd A. Blobel, Edward J. Banigan, Anders S. Hansen","doi":"10.1038/s41594-025-01687-2","DOIUrl":"10.1038/s41594-025-01687-2","url":null,"abstract":"As cells exit mitosis and enter G1, chromosomes decompact and transcription is reestablished. Hi-C studies have indicated that all interphase three-dimensional genome features, including A/B compartments, topologically associating domains and CCCTC-binding factor loops, are lost during mitosis. However, Hi-C is insensitive to features such as microcompartments, nested focal interactions between cis-regulatory elements. Here we apply region capture Micro-C to mouse erythroblasts from mitosis to G1. We unexpectedly observe microcompartments in prometaphase, which strengthen in anaphase and telophase before weakening throughout G1. Microcompartment anchors coincide with transcriptionally spiking promoters during mitosis. Loss of condensin loop extrusion differentially impacts microcompartments and A/B compartments, suggesting that they are partially distinct. Polymer modeling shows that microcompartment formation is favored by chromatin compaction and disfavored by loop extrusion, providing a basis for strong microcompartmentalization in anaphase and telophase. Our results suggest that compaction and homotypic affinity drive microcompartment formation, which may explain transient transcriptional spiking at mitotic exit. Goel et al. produce high-resolution three-dimensional genome structure mapping from mitosis to G1 phase to show unseen interactions between enhancers and promoters in prometaphase. Polymer modeling indicates the interactions are facilitated by chromosome compaction.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2614-2627"},"PeriodicalIF":10.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01687-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313339","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}
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