Pub Date : 2025-11-20DOI: 10.1016/j.molcel.2025.10.030
Guodi Cai, Zhenhua Zhang, Lin Zhong, Hong Wang, Miaomiao Miao, Jingtian Su, Yana An, Chenxi Zhang, Xiaowei Luo, Huai-Qiang Ju, Jian Zhang, Wanyi Huang, Zhe Li, Peiqing Liu, Dinglan Wu, Franky Leung Chan, Huihao Zhou, Fanghai Han, Hong-Wu Chen, Tao Su, Junjian Wang
Nucleotide metabolism reprogramming drives tumor progression, yet how tumor cells sense nucleotide levels remains unclear. Here, we identified UMP as an endogenous regulator of the orphan nuclear receptor NR4A1 in gastric cancer (GCa). Under UMP sufficiency, UMP directly binds to NR4A1, inhibiting its tumor-suppressive function and promoting GCa progression. Conversely, UMP deficiency resulting from disrupted pyrimidine biosynthesis derepresses NR4A1, which suppresses GCa cell survival and progression by both increasing NR4A1 occupancy at super-enhancers to reprogram survival-gene expression and enhancing NR4A1’s pro-apoptotic activity at the mitochondria. NR4A1 loss was sufficient to rescue the effects of pyrimidine nucleotide stress on GCa cells in vitro and in vivo. NR4A1 agonists suppressed the pyrimidine salvage pathway triggered by de novo pyrimidine biosynthesis (DNPB) inhibition. Co-targeting DNPB and NR4A1 induced synergistic tumor lethality in GCa xenograft models. Together, our results establish UMP as an endogenous regulator of NR4A1 and provide an effective therapeutic strategy for GCa.
{"title":"UMP functions as an endogenous regulator of NR4A1 to control gastric cancer progression","authors":"Guodi Cai, Zhenhua Zhang, Lin Zhong, Hong Wang, Miaomiao Miao, Jingtian Su, Yana An, Chenxi Zhang, Xiaowei Luo, Huai-Qiang Ju, Jian Zhang, Wanyi Huang, Zhe Li, Peiqing Liu, Dinglan Wu, Franky Leung Chan, Huihao Zhou, Fanghai Han, Hong-Wu Chen, Tao Su, Junjian Wang","doi":"10.1016/j.molcel.2025.10.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.030","url":null,"abstract":"Nucleotide metabolism reprogramming drives tumor progression, yet how tumor cells sense nucleotide levels remains unclear. Here, we identified UMP as an endogenous regulator of the orphan nuclear receptor NR4A1 in gastric cancer (GCa). Under UMP sufficiency, UMP directly binds to NR4A1, inhibiting its tumor-suppressive function and promoting GCa progression. Conversely, UMP deficiency resulting from disrupted pyrimidine biosynthesis derepresses NR4A1, which suppresses GCa cell survival and progression by both increasing NR4A1 occupancy at super-enhancers to reprogram survival-gene expression and enhancing NR4A1’s pro-apoptotic activity at the mitochondria. NR4A1 loss was sufficient to rescue the effects of pyrimidine nucleotide stress on GCa cells <em>in vitro</em> and <em>in vivo</em>. NR4A1 agonists suppressed the pyrimidine salvage pathway triggered by <em>de novo</em> pyrimidine biosynthesis (DNPB) inhibition. Co-targeting DNPB and NR4A1 induced synergistic tumor lethality in GCa xenograft models. Together, our results establish UMP as an endogenous regulator of NR4A1 and provide an effective therapeutic strategy for GCa.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"160 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554800","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 : 2025-11-20DOI: 10.1016/j.molcel.2025.10.032
Morris F. White
Wang et al.1 use innovative computational methods to design polypeptides that bind to and activate the insulin receptor tyrosine kinase, revealing strategies to resolve the composite insulin signal into distinct components for therapeutic use.
{"title":"A new horizon unfolding for insulin signaling in health and disease","authors":"Morris F. White","doi":"10.1016/j.molcel.2025.10.032","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.032","url":null,"abstract":"Wang et al.<span><span><sup>1</sup></span></span> use innovative computational methods to design polypeptides that bind to and activate the insulin receptor tyrosine kinase, revealing strategies to resolve the composite insulin signal into distinct components for therapeutic use.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"82 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554803","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 : 2025-11-20DOI: 10.1016/j.molcel.2025.10.029
Michaela Müller-McNicoll
Recent work by Faraway et al.1 uncovers interstasis—a feedback mechanism whereby the stiffening of nuclear condensates caused by the accumulation of condensation-prone resident proteins entraps mRNAs encoding these proteins, thereby limiting their translation to restore proteome balance.
{"title":"Getting sticky: How nuclear speckles tune the condensation-prone proteome","authors":"Michaela Müller-McNicoll","doi":"10.1016/j.molcel.2025.10.029","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.029","url":null,"abstract":"Recent work by Faraway et al.<span><span><sup>1</sup></span></span> uncovers interstasis—a feedback mechanism whereby the stiffening of nuclear condensates caused by the accumulation of condensation-prone resident proteins entraps mRNAs encoding these proteins, thereby limiting their translation to restore proteome balance.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"41 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554805","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 : 2025-11-20DOI: 10.1016/j.molcel.2025.10.023
Yi Di, Wenxue Li, Joan Josep Castellano, Wenjie Jin, Joanna N. Modi, Barbora Salovska, Delyar Khosroabadi, Wei Hu, Alison M. Taylor, Yansheng Liu
How aneuploid cells tolerate chromosome arm gains or losses remains an open question. Using an isogenic human lung cell model with either chromosome 3p loss or 3q gain, combined with quantitative mass spectrometry and isotopic labeling, we reveal distinct proteostasis mechanisms for gain- and loss-type aneuploidy. Surprisingly, while compensation for 3q gain is primarily driven by increased degradation of excess protein complex subunits, 3p loss is neither counteracted by global protein degradation nor selectively reduced degradation. Rather, there is a relative upregulation in protein synthesis of those 3p-encoded proteins that participate in stable protein complexes to maintain functional complex stoichiometry. Additionally, 3p-encoded proteins that are in a complex show increased thermal stability in loss-type aneuploidy, potentially via their interactions with other proteins from euploid chromosomes. Together, our findings uncover distinct proteomic buffering strategies that enable cells to tolerate either excessive or deficient single-arm aneuploidy.
{"title":"Divergent proteome tolerance against gain and loss of chromosome arms","authors":"Yi Di, Wenxue Li, Joan Josep Castellano, Wenjie Jin, Joanna N. Modi, Barbora Salovska, Delyar Khosroabadi, Wei Hu, Alison M. Taylor, Yansheng Liu","doi":"10.1016/j.molcel.2025.10.023","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.023","url":null,"abstract":"How aneuploid cells tolerate chromosome arm gains or losses remains an open question. Using an isogenic human lung cell model with either chromosome <em>3p loss</em> or <em>3q gain</em>, combined with quantitative mass spectrometry and isotopic labeling, we reveal distinct proteostasis mechanisms for gain- and loss-type aneuploidy. Surprisingly, while compensation for <em>3q gain</em> is primarily driven by increased degradation of excess protein complex subunits, <em>3p loss</em> is neither counteracted by global protein degradation nor selectively reduced degradation. Rather, there is a relative upregulation in protein synthesis of those 3p-encoded proteins that participate in stable protein complexes to maintain functional complex stoichiometry. Additionally, 3p-encoded proteins that are in a complex show increased thermal stability in loss-type aneuploidy, potentially via their interactions with other proteins from euploid chromosomes. Together, our findings uncover distinct proteomic buffering strategies that enable cells to tolerate either excessive or deficient single-arm aneuploidy.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"20 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554808","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 : 2025-11-20DOI: 10.1016/j.molcel.2025.10.020
Timothy C. Kenny, Kıvanç Birsoy
In this issue of Molecular Cell, Nengroo et al.1 report that the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is essential for de novo purine synthesis, revealing a previously unrecognized metabolic dependency in cancer that can be leveraged therapeutically.
{"title":"Succinate puts the brakes on de novo purine synthesis","authors":"Timothy C. Kenny, Kıvanç Birsoy","doi":"10.1016/j.molcel.2025.10.020","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.020","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, Nengroo et al.<span><span><sup>1</sup></span></span> report that the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is essential for <em>de novo</em> purine synthesis, revealing a previously unrecognized metabolic dependency in cancer that can be leveraged therapeutically.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"147 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554855","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 : 2025-11-20DOI: 10.1016/j.molcel.2025.10.024
Daniela Barillà
Asgard archaea are widely considered the closest living relatives of eukaryotes. In this issue of Molecular Cell, Ranawat et al.1 report high-resolution structures of hypernucleosomes formed by the hodarchaeal HHoB histone, disclosing open and closed chromatin conformations.
{"title":"Let’s wrap things up: Open and closed hypernucleosomes in Asgard archaea","authors":"Daniela Barillà","doi":"10.1016/j.molcel.2025.10.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.024","url":null,"abstract":"Asgard archaea are widely considered the closest living relatives of eukaryotes. In this issue of <em>Molecular Cell</em>, Ranawat et al.<span><span><sup>1</sup></span></span> report high-resolution structures of hypernucleosomes formed by the hodarchaeal HHoB histone, disclosing open and closed chromatin conformations.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554802","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 : 2025-11-20DOI: 10.1016/j.molcel.2025.10.031
Emeline Joulia, Christian M. Metallo
In a recent Nature article, Xiao et al.1 report development of a metabolite-protein covariation architecture (MPCA) database from a diversity outbred mouse cohort that facilitates the deciphering of metabolite-protein relationships in liver and brown adipose tissue (BAT). Using these correlations, the authors describe a role for LRRC58 in controlling cysteine-taurine metabolism.
{"title":"Leveraging biochemical covariance to better understand biology","authors":"Emeline Joulia, Christian M. Metallo","doi":"10.1016/j.molcel.2025.10.031","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.031","url":null,"abstract":"In a recent <em>Nature</em> article, Xiao et al.<span><span><sup>1</sup></span></span> report development of a metabolite-protein covariation architecture (MPCA) database from a diversity outbred mouse cohort that facilitates the deciphering of metabolite-protein relationships in liver and brown adipose tissue (BAT). Using these correlations, the authors describe a role for LRRC58 in controlling cysteine-taurine metabolism.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"28 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554804","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 : 2025-11-20DOI: 10.1016/j.molcel.2025.10.028
Stephanie Patchett, Seyed Arad Moghadasi, Ankita Shukla, Farid El Oualid, Beatrix M. Ueberheide, Shaun K. Olsen, Tony T. Huang
In eukaryotes, each ribosomal subunit includes a ribosomal protein (RP) that is encoded as a fusion protein with ubiquitin (Ub). In yeast, each Ub-RP fusion requires processing by deubiquitylating enzymes (DUBs) to generate ribosome assembly-competent RPs and contribute to the cellular Ub pool. However, how Ub-RP fusions are processed by DUBs in human cells remains unclear. Here, we discovered that Ub-RPs are substrates of the Ub-fusion degradation (UFD) pathway in human cells via lysine 29 and 48 (K29/K48)-specific ubiquitylation and proteasomal degradation. We identified a pool of DUBs that catalytically process Ub-RPs, as well as DUBs that physically occlude Ub-RP interaction with UFD pathway Ub E3 ligases to prevent their degradation in a non-catalytic manner. Our results suggest that DUBs both process and stabilize Ub-RPs, whereas the UFD pathway regulates levels of Ub-RPs that cannot be fully processed by DUBs to fine-tune protein homeostasis.
{"title":"Deubiquitinases cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway","authors":"Stephanie Patchett, Seyed Arad Moghadasi, Ankita Shukla, Farid El Oualid, Beatrix M. Ueberheide, Shaun K. Olsen, Tony T. Huang","doi":"10.1016/j.molcel.2025.10.028","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.028","url":null,"abstract":"In eukaryotes, each ribosomal subunit includes a ribosomal protein (RP) that is encoded as a fusion protein with ubiquitin (Ub). In yeast, each Ub-RP fusion requires processing by deubiquitylating enzymes (DUBs) to generate ribosome assembly-competent RPs and contribute to the cellular Ub pool. However, how Ub-RP fusions are processed by DUBs in human cells remains unclear. Here, we discovered that Ub-RPs are substrates of the Ub-fusion degradation (UFD) pathway in human cells via lysine 29 and 48 (K29/K48)-specific ubiquitylation and proteasomal degradation. We identified a pool of DUBs that catalytically process Ub-RPs, as well as DUBs that physically occlude Ub-RP interaction with UFD pathway Ub E3 ligases to prevent their degradation in a non-catalytic manner. Our results suggest that DUBs both process and stabilize Ub-RPs, whereas the UFD pathway regulates levels of Ub-RPs that cannot be fully processed by DUBs to fine-tune protein homeostasis.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"19 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554812","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 : 2025-11-19DOI: 10.1016/j.molcel.2025.10.026
Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras
Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety of the BRCT domain, HSP90 reduces the clinical severity of BRCA1 mutations, allowing them to accumulate in populations. We estimate that HSP90 buffers 18% of known human BRCA1-BRCT missense mutations. Our work extends the clinical significance of HSP90 buffering to a prevalent class of variations in BRCA1, pioneering its importance in therapy resistance and cancer predisposition.
{"title":"HSP90 buffers deleterious genetic variations in BRCA1","authors":"Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras","doi":"10.1016/j.molcel.2025.10.026","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.026","url":null,"abstract":"Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered <em>BRCA1</em> mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety of the BRCT domain, HSP90 reduces the clinical severity of <em>BRCA1</em> mutations, allowing them to accumulate in populations. We estimate that HSP90 buffers 18% of known human BRCA1-BRCT missense mutations. Our work extends the clinical significance of HSP90 buffering to a prevalent class of variations in <em>BRCA1</em>, pioneering its importance in therapy resistance and cancer predisposition.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"8 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545665","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 : 2025-11-18DOI: 10.1016/j.molcel.2025.10.025
Rayees U.H. Mattoo, Dong-Hua Chen, David A. Bushnell, Sagi Tamir, Roger D. Kornberg
The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, a 1.8 MDa multi-subunit assembly comprising 19 subunits, is required for RNA polymerase II transcription in eukaryotes. The complex consists of four modules: transcription-associated protein 1 (Tra1), core, deubiquitination (DUB), and histone acetyltransferase (HAT). Although the structures of the Tra1, core, and DUB modules have been determined, the overall architecture of the HAT module remained elusive due to its inherent flexibility. To address this, we conducted cryo-electron microscopy (cryo-EM) analyses on SAGA purified from the thermophilic fungus Chaetomium thermophilum, yielding structures of Tra1 and core modules at 2.6 Å and three of the four HAT subunits at 3.7 Å. The structure of the HAT module was informative about the aspects of histone acetylation and the interface of HAT-core modules, contradicting earlier AlphaFold predictions. Our structure-guided genetic and biochemical analyses confirmed the roles of Ada1 and Spt7 in anchoring the HAT module within the SAGA complex.
{"title":"Structure of the transcriptional co-activator SAGA complex, including the histone acetyltransferase module","authors":"Rayees U.H. Mattoo, Dong-Hua Chen, David A. Bushnell, Sagi Tamir, Roger D. Kornberg","doi":"10.1016/j.molcel.2025.10.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.10.025","url":null,"abstract":"The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex, a 1.8 MDa multi-subunit assembly comprising 19 subunits, is required for RNA polymerase II transcription in eukaryotes. The complex consists of four modules: transcription-associated protein 1 (Tra1), core, deubiquitination (DUB), and histone acetyltransferase (HAT). Although the structures of the Tra1, core, and DUB modules have been determined, the overall architecture of the HAT module remained elusive due to its inherent flexibility. To address this, we conducted cryo-electron microscopy (cryo-EM) analyses on SAGA purified from the thermophilic fungus <em>Chaetomium thermophilum</em>, yielding structures of Tra1 and core modules at 2.6 Å and three of the four HAT subunits at 3.7 Å. The structure of the HAT module was informative about the aspects of histone acetylation and the interface of HAT-core modules, contradicting earlier AlphaFold predictions. Our structure-guided genetic and biochemical analyses confirmed the roles of Ada1 and Spt7 in anchoring the HAT module within the SAGA complex.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"6 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536473","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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