Molecular Systems Biology最新文献

Compensatory evolution to DNA replication stress is robust to nutrient availability. DNA复制胁迫的代偿性进化对营养物质的可利用性是稳健的。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-26 DOI: 10.1038/s44320-025-00127-z

Mariana Natalino, Marco Fumasoni

{"title":"Compensatory evolution to DNA replication stress is robust to nutrient availability.","authors":"Mariana Natalino, Marco Fumasoni","doi":"10.1038/s44320-025-00127-z","DOIUrl":"https://doi.org/10.1038/s44320-025-00127-z","url":null,"abstract":"Evolutionary repair refers to the compensatory evolution that follows perturbations in cellular processes. While evolutionary trajectories are often reproducible, other studies suggest they are shaped by genotype-by-environment (GxE) interactions. Here, we test the predictability of evolutionary repair in response to DNA replication stress-a severe perturbation impairing the conserved mechanisms of DNA synthesis, resulting in genetic instability. We conducted high-throughput experimental evolution on Saccharomyces cerevisiae experiencing constitutive replication stress, grown under different glucose availability. We found that glucose levels impact the physiology and adaptation rate of replication stress mutants. However, the genetics of adaptation show remarkable robustness across environments. Recurrent mutations collectively recapitulated the fitness of evolved lines and are advantageous across macronutrient availability. We also identified a novel role of the mediator complex of RNA polymerase II in adaptation to replicative stress. Our results highlight the robustness and predictability of evolutionary repair mechanisms to DNA replication stress and provide new insights into the evolutionary aspects of genome stability, with potential implications for understanding cancer development.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From microbes to molecules: unveiling host-microbe interactions with spatial metabolomics. 从微生物到分子：揭示宿主-微生物与空间代谢组学的相互作用。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-24 DOI: 10.1038/s44320-025-00129-x

Malin Stüwe, Lars-Erik Petersen, Manuel Liebeke

引用次数: 0

AlphaDesign: a de novo protein design framework based on AlphaFold. AlphaDesign：基于AlphaFold的全新蛋白质设计框架。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-17 DOI: 10.1038/s44320-025-00119-z

Michael A Jendrusch, Alessio L J Yang, Elisabetta Cacace, Jacob Bobonis, Carlos G P Voogdt, Sarah Kaspar, Kristian Schweimer, Cecilia Perez-Borrajero, Karine Lapouge, Jacob Scheurich, Kim Remans, Janosch Hennig, Athanasios Typas, Jan O Korbel, S Kashif Sadiq

引用次数: 0

Author Correction: Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis. 作者更正：雌激素受体激活重塑TEAD1基因表达，减轻肝脂肪变性。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-11 DOI: 10.1038/s44320-025-00126-0

Christian Sommerauer, Carlos J Gallardo-Dodd, Christina Savva, Linnea Hases, Madeleine Birgersson, Rajitha Indukuri, Joanne X Shen, Pablo Carravilla, Keyi Geng, Jonas Nørskov Søndergaard, Clàudia Ferrer-Aumatell, Grégoire Mercier, Erdinc Sezgin, Marion Korach-André, Carl Petersson, Hannes Hagström, Volker M Lauschke, Amena Archer, Cecilia Williams, Claudia Kutter

引用次数: 0

Orthogonal replication with optogenetic selection evolves yeast JEN1 into a mevalonate transporter. 光遗传选择的正交复制使酵母菌JEN1成为甲羟戊酸转运蛋白。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-11 DOI: 10.1038/s44320-025-00113-5

Scott A Wegner, Virginia Jiang, Jeremy D Cortez, José L Avalos

{"title":"Orthogonal replication with optogenetic selection evolves yeast JEN1 into a mevalonate transporter.","authors":"Scott A Wegner, Virginia Jiang, Jeremy D Cortez, José L Avalos","doi":"10.1038/s44320-025-00113-5","DOIUrl":"https://doi.org/10.1038/s44320-025-00113-5","url":null,"abstract":"The in vivo continuous evolution system OrthoRep (orthogonal replication) is a powerful strategy for rapid enzyme evolution in Saccharomyces cerevisiae that diversifies genes at a rate exceeding the endogenous genome mutagenesis rate by several orders of magnitude. However, it is difficult to neofunctionalize genes using OrthoRep partly because of the way selection pressures are applied. Here we combine OrthoRep with optogenetics in a selection strategy we call OptoRep, which allows fine-tuning of selection pressure with light. With this capability, we evolved a truncated form of the endogenous monocarboxylate transporter JEN1 (JEN1t) into a de novo mevalonate importer. We demonstrate the functionality of the evolved JEN1t (JEN1tY180C/G) in the production of farnesene, a renewable aviation biofuel, from mevalonate fed to fermentation media or produced by microbial consortia. This study shows that the light-induced complementation of OptoRep may improve the ability to evolve functions not currently accessible for selection, while its fine tunability of selection pressure may allow the continuous evolution of genes whose desired function has a restrictive range between providing effective selection and cellular viability.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Signalomics for molecular tumor boards and precision oncology of breast and gynecological cancers. 信号组学用于乳腺癌和妇科肿瘤的分子肿瘤板和精确肿瘤学。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-09 DOI: 10.1038/s44320-025-00125-1

Tatiana V Denisenko, Anna E Ivanova, Alexey Koval, Denis N Silachev, Lee Jia, Gennadiy T Sukhikh, Vladimir L Katanaev

{"title":"Signalomics for molecular tumor boards and precision oncology of breast and gynecological cancers.","authors":"Tatiana V Denisenko, Anna E Ivanova, Alexey Koval, Denis N Silachev, Lee Jia, Gennadiy T Sukhikh, Vladimir L Katanaev","doi":"10.1038/s44320-025-00125-1","DOIUrl":"https://doi.org/10.1038/s44320-025-00125-1","url":null,"abstract":"Precision oncology led to the establishment and widespread application of molecular tumor boards (MTBs)-multidisciplinary units combining molecular and clinical assessment of individual cancer cases for swift selection of personalized treatments. Whole-exome or gene panel sequencing, combined with transcriptomic, immunohistochemical, and other molecular analyses, often permits dissection of molecular drivers of a tumor and identification of its potential targetable vulnerabilities, instructing clinical oncologists on sometimes unconventional treatment options. However, cancer drivers are often unleashed mutation-independently, especially in breast and gynecological cancers, and deleterious mutations are not always pathogenic. To complement the MTB arsenal, we chart here the molecular toolset we call Signalomics that permits fast and robust assessment of a panel of oncogenic signaling pathways in fresh tumor samples. Using transcriptional reporters introduced in primary tumor cells, this approach identifies the pathways overactivated in a given tumor and validates their sensitivity to targeted therapies, providing actionable insights for personalized treatment strategies. Integration of Signalomics into MTB workflows bridges the gap between molecular profiling and functional pathway analysis, refining clinical treatment decisions and advancing precision oncology.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A transient mutational burst occurs during yeast colony development. 在酵母菌落发育过程中会发生短暂的突变爆发。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-09 DOI: 10.1038/s44320-025-00117-1

Nicolas Agier, Nina Vittorelli, Louis Ollivier, Frédéric Chaux, Alexandre Gillet-Markowska, Samuel O'Donnell, Fanny Pouyet, Gilles Fischer, Stéphane Delmas

{"title":"A transient mutational burst occurs during yeast colony development.","authors":"Nicolas Agier, Nina Vittorelli, Louis Ollivier, Frédéric Chaux, Alexandre Gillet-Markowska, Samuel O'Donnell, Fanny Pouyet, Gilles Fischer, Stéphane Delmas","doi":"10.1038/s44320-025-00117-1","DOIUrl":"https://doi.org/10.1038/s44320-025-00117-1","url":null,"abstract":"Characterizing the contribution of mutators to mutation accumulation is essential for understanding cellular adaptation and diseases like cancer. By measuring single and double mutation rates, including point mutations, segmental duplications, and reciprocal translocations, we found that wild-type yeast colonies exhibit double mutation rates up to 17 times higher than expected from experimentally determined single mutation rates. These double mutants retained wild-type mutation rates, indicating they originated from genetically normal cells that transiently expressed a mutator phenotype. Numerical simulations suggest that transient mutator subpopulations likely consist of less than a few thousand cells, and experience high-intensity mutational bursts for less than five generations. Most double mutations accumulated sequentially across cell cycles, with simultaneous acquisition being rare and likely linked to systemic genomic instability. Additionally, we explored the genetic control of transient hypermutation and found that the excess of double mutants can be modulated by replication stress and the DNA damage tolerance pathway. Our findings suggest that transient mutators play a significant role in genomic instability and contribute to the mutational load accumulating in growing isogenic populations.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A discovery platform for identification of host-induced bacterial biosensors from diverse sources. 一个发现平台，用于鉴定来自不同来源的宿主诱导的细菌生物传感器。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-09 DOI: 10.1038/s44320-025-00123-3

Clare M Robinson, David Carreño, Tim Weber, Yangyumeng Chen, David T Riglar

{"title":"A discovery platform for identification of host-induced bacterial biosensors from diverse sources.","authors":"Clare M Robinson, David Carreño, Tim Weber, Yangyumeng Chen, David T Riglar","doi":"10.1038/s44320-025-00123-3","DOIUrl":"https://doi.org/10.1038/s44320-025-00123-3","url":null,"abstract":"Synthetic biology approaches such as whole-cell biosensing and 'sense-and-respond' therapeutics aim to enlist the vast sensing repertoire of gut microbes to drive cutting-edge clinical and research applications. However, well-characterised circuit components that sense health- and disease-relevant conditions within the gut remain limited. Here, we extend the flexibility and power of a biosensor screening platform using bacterial memory circuits. We construct libraries of sensory components sourced from diverse gut bacteria using a bespoke two-component system identification and cloning pipeline. Tagging unique strains using a hypervariable DNA barcode enables parallel tracking of thousands of unique clones, corresponding to ~150 putative biosensors, in a single experiment. Evaluating sensor activity and performance heterogeneity across various in vitro and in vivo conditions using mouse models, we identify several biosensors of interest. Validated hits include biosensors with relevance for autonomous control of synthetic functions within the mammalian gut and for non-invasive monitoring of inflammatory disease using faecal sampling. This approach will promote rapid biosensor engineering to advance the development of synthetic biology tools for deployment within complex environments.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells. 途径代谢物比率揭示了增殖细胞子集中独特的谷氨酰胺代谢。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-05 DOI: 10.1038/s44320-025-00099-0

Nancy T Santiappillai, Yue Cao, Mariam F Hakeem-Sanni, Jean Yang, Lake-Ee Quek, Andrew J Hoy

{"title":"Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells.","authors":"Nancy T Santiappillai, Yue Cao, Mariam F Hakeem-Sanni, Jean Yang, Lake-Ee Quek, Andrew J Hoy","doi":"10.1038/s44320-025-00099-0","DOIUrl":"https://doi.org/10.1038/s44320-025-00099-0","url":null,"abstract":"Large-scale metabolomic analyses of pan-cancer cell line panels have provided significant insights into the relationships between metabolism and cancer cell biology. Here, we took a pathway-centric approach by transforming targeted metabolomic data into ratios to study associations between reactant and product metabolites in a panel of cancer and non-cancer cell lines. We identified five clusters of cells from various tissue origins. Of these, cells in Cluster 4 had high ratios of TCA cycle metabolites relative to pyruvate, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios. This was due to more glutamine cataplerotic efflux and not glycolysis in cells of Cluster 4. In silico analyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of glutamine metabolism and OXPHOS than cells in Cluster 3. Our results highlight the potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion. 控制b细胞群扩增的BCR和CD40信号整合中的协同和拮抗作用。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2025-06-05 DOI: 10.1038/s44320-025-00124-2

Helen Huang, Haripriya Vaidehi Narayanan, Mark Yankai Xiang, Vaibhava Kesarwani, Alexander Hoffmann

{"title":"Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion.","authors":"Helen Huang, Haripriya Vaidehi Narayanan, Mark Yankai Xiang, Vaibhava Kesarwani, Alexander Hoffmann","doi":"10.1038/s44320-025-00124-2","DOIUrl":"10.1038/s44320-025-00124-2","url":null,"abstract":"In response to infection or vaccination, lymph nodes must select antigen-reactive B-cells while eliminating auto-reactive B-cells. B-cells are instructed via B-cell receptor (BCR), which binds antigen, and CD40 receptor by antigen-recognizing T-cells. How BCR and CD40 signaling are integrated quantitatively to jointly determine B-cell fate decisions remains unclear. Here, we developed a differential-equations-based model of BCR and CD40 signaling networks activating NFκB. The model recapitulates NFκB dynamics upon BCR and CD40 stimulation, and when linked to established cell decision models of cell cycle and survival control, the resulting cell population dynamics. However, upon costimulation, NFκB dynamics were correctly predicted but the predicted potentiated population expansion was not observed experimentally. We found that this discrepancy was due to BCR-induced caspase activity that may trigger apoptosis in founder cells, unless timely NFκB-induced survival gene expression protects them. Iterative model predictions and sequential co-stimulation experiments revealed how complex non-monotonic integration of BCR and CD40 signals controls positive and negative selection of B-cells. Our work suggests a temporal proof-reading mechanism for regulating the stringency of B-cell selection during antibody responses.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":8.5,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0