Transcription of protein-coding genes by RNA polymerase II involves a characteristic pausing event downstream from transcription start sites. Such promoter-proximal pausing likely represents a transcription checkpoint, which ensures proper assembly of a fully functional RNAPII elongation complex that is capable of transcribing through the chromatin environment, with correctly modified nascent pre-mRNA. Failure to negotiate this promoter-proximal checkpoint results in termination of transcription and removal of RNAPII from the DNA. This review summarizes current knowledge on the mechanisms that regulate promoter-proximal pausing, maturation of the elongation complex, and the decision of whether to license RNAPII for elongation or prematurely terminate transcription.
{"title":"Transcription quality control at the promoter-proximal checkpoint","authors":"Daniel Blears, Jesper Q. Svejstrup","doi":"10.1101/gad.352973.125","DOIUrl":"https://doi.org/10.1101/gad.352973.125","url":null,"abstract":"Transcription of protein-coding genes by RNA polymerase II involves a characteristic pausing event downstream from transcription start sites. Such promoter-proximal pausing likely represents a transcription checkpoint, which ensures proper assembly of a fully functional RNAPII elongation complex that is capable of transcribing through the chromatin environment, with correctly modified nascent pre-mRNA. Failure to negotiate this promoter-proximal checkpoint results in termination of transcription and removal of RNAPII from the DNA. This review summarizes current knowledge on the mechanisms that regulate promoter-proximal pausing, maturation of the elongation complex, and the decision of whether to license RNAPII for elongation or prematurely terminate transcription.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"11 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089445","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}
Raúl Sánchez-Vázquez, Sonia Burgaz García-Oteyza, Rosa Serrano, Juana M. Flores, Paula Martínez, Maria A. Blasco
Pulmonary fibrosis is a lethal disease associated with damaging insults to the lung and with organismal aging. The presence of short and dysfunctional telomeres has been placed at the origin of this disease in a percentage of both familial and sporadic cases. Recently, a mutation in the telomere-binding protein protection of telomeres 1 in humans (hPOT1), the hPOT1 L259S mutation, was found in families with idiopathic pulmonary fibrosis. Here, we generated a Pot1aL261S knock-in mouse harboring the murine homologous hPOT1 L259S mutation. We found that the homozygous Pot1aL261S mice show shorter telomeres and degenerative pathologies in the intestine, testes, and lungs at old ages, a phenotype that is aggravated with increasing mouse generations, in striking analogy to the telomerase-deficient mouse models. Furthermore, we found that the POT1a-L261S mutant protein binds more strongly to TPP1 and to telomerase and impedes telomerase-dependent telomere lengthening in vivo. We show that telomerase activity at telomeres is reduced in the presence of POT1a-L261S, which behaves as a dominant negative mutant, thus providing a potential mechanism by which Pot1aL261S knock-in mice phenocopy the short telomere phenotype of the telomerase knockout model.
{"title":"Mice carrying the homologous human shelterin POT1-L259S mutation linked to pulmonary fibrosis show a telomerase deficiency-like phenotype with telomere shortening with increasing mouse generations","authors":"Raúl Sánchez-Vázquez, Sonia Burgaz García-Oteyza, Rosa Serrano, Juana M. Flores, Paula Martínez, Maria A. Blasco","doi":"10.1101/gad.352855.125","DOIUrl":"https://doi.org/10.1101/gad.352855.125","url":null,"abstract":"Pulmonary fibrosis is a lethal disease associated with damaging insults to the lung and with organismal aging. The presence of short and dysfunctional telomeres has been placed at the origin of this disease in a percentage of both familial and sporadic cases. Recently, a mutation in the telomere-binding protein <em>protection of telomeres 1</em> in humans (<em>hPOT1</em>), the <em>hPOT1 L259S</em> mutation, was found in families with idiopathic pulmonary fibrosis. Here, we generated a <em>Pot1a</em><sup><em>L261S</em></sup> knock-in mouse harboring the murine homologous <em>hPOT1 L259S</em> mutation. We found that the homozygous <em>Pot1a</em><sup><em>L261S</em></sup> mice show shorter telomeres and degenerative pathologies in the intestine, testes, and lungs at old ages, a phenotype that is aggravated with increasing mouse generations, in striking analogy to the telomerase-deficient mouse models. Furthermore, we found that the POT1a-L261S mutant protein binds more strongly to TPP1 and to telomerase and impedes telomerase-dependent telomere lengthening in vivo. We show that telomerase activity at telomeres is reduced in the presence of POT1a-L261S, which behaves as a dominant negative mutant, thus providing a potential mechanism by which <em>Pot1a</em><sup><em>L261S</em></sup> knock-in mice phenocopy the short telomere phenotype of the telomerase knockout model.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"67 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067757","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}
Adipose tissue is rapidly expanding early in life. Elucidating the queues facilitating this process will advance our understanding of metabolically healthy obesity. Using single-cell RNA sequencing, we identified compositional differences of prewean and adult murine subcutaneous adipose tissue. We identified a dipeptidyl peptidase-4 (Dpp4)-positive precursor population residing in the reticular interstitium of subcutaneous adipose expressing insulin growth factor 2 (Igf2) in prewean mice. We show that IGF2 drives proliferation rather than differentiation in these cells. Moreover, loss of Igf2 in Dpp4+ progenitor cells promotes adipogenesis. Our findings unravel the temporally restricted expression of Igf2 to promote preadipocyte expansion.
{"title":"Igf2 regulates early postnatal DPP4+ preadipocyte pool expansion","authors":"Irem Altun, Khanh Ho Diep Vo, Safal Walia, Xiaocheng Yan, Inderjeet Singh, Ruth Karlina, Viktorian Miok, Lingru Kang, Valentin Kenneth Reichenbach, Andreas Israel, Dominik Lutter, Fabiana Perrochi, Siegfried Ussar","doi":"10.1101/gad.352710.125","DOIUrl":"https://doi.org/10.1101/gad.352710.125","url":null,"abstract":"Adipose tissue is rapidly expanding early in life. Elucidating the queues facilitating this process will advance our understanding of metabolically healthy obesity. Using single-cell RNA sequencing, we identified compositional differences of prewean and adult murine subcutaneous adipose tissue. We identified a dipeptidyl peptidase-4 (<em>Dpp4</em>)-positive precursor population residing in the reticular interstitium of subcutaneous adipose expressing insulin growth factor 2 (<em>Igf2</em>) in prewean mice. We show that IGF2 drives proliferation rather than differentiation in these cells. Moreover, loss of <em>Igf2</em> in <em>Dpp4</em><sup>+</sup> progenitor cells promotes adipogenesis. Our findings unravel the temporally restricted expression of <em>Igf2</em> to promote preadipocyte expansion.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"308 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031926","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}
Davys H. Lopez, Kevin D. Rostam, Sumaira Zamurrad, Shuwa Xu, Richard S. Mann
For neurons to establish the correct connections in animal nervous systems, interactions between cell adhesion molecules (CAMs), expressed presynaptically and postsynaptically, are thought to guide neurons to their targets. Here, we assess the role that affinity between two cognate CAMs—DIP-α and Dpr10—plays in establishing the leg neuromuscular system in Drosophila. If affinity decreases or, surprisingly, increases past certain thresholds, motor neuron (MN) terminal branches fail to be maintained. Live imaging during development shows that when affinities are aberrant, MN filopodia are unable to productively engage their muscle targets. Thus, CAM affinities are tuned to achieve proper neuronal morphology.
{"title":"A critical affinity window for IgSF proteins DIP-α and Dpr10 is required for proper motor neuron arborization","authors":"Davys H. Lopez, Kevin D. Rostam, Sumaira Zamurrad, Shuwa Xu, Richard S. Mann","doi":"10.1101/gad.352936.125","DOIUrl":"https://doi.org/10.1101/gad.352936.125","url":null,"abstract":"For neurons to establish the correct connections in animal nervous systems, interactions between cell adhesion molecules (CAMs), expressed presynaptically and postsynaptically, are thought to guide neurons to their targets. Here, we assess the role that affinity between two cognate CAMs—DIP-α and Dpr10—plays in establishing the leg neuromuscular system in <em>Drosophila</em>. If affinity decreases or, surprisingly, increases past certain thresholds, motor neuron (MN) terminal branches fail to be maintained. Live imaging during development shows that when affinities are aberrant, MN filopodia are unable to productively engage their muscle targets. Thus, CAM affinities are tuned to achieve proper neuronal morphology.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"25 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031944","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}
Pavel A. Vlasov, Koichi Ogami, Elizabeth Valenzuela, Risa Karakida Kawaguchi, Marko Jovanovic, James L. Manley
Enhancer RNAs (eRNAs) are transcribed by RNA polymerase IIduring enhancer activation but are typically rapidly degraded in the nucleus. During states of reduced RNA surveillance, however, eRNAs and other similar “noncoding” RNAs (including, e.g., upstream antisense RNAs) are stabilized, and some are exported to the cytoplasm and can even be found on polysomes. Here, we report unexpectedly that ∼12% of human intergenic eRNAs contain long open reading frames (>300 nt), many of which can be actively translated, as determined by ribosome profiling, and produce proteins that accumulate in cells, as shown by mass spectrometry (MS) data. Focusing on the largest of the encoded proteins, which we designated as eORFs, which can be up to ∼45 kDa, we found, remarkably, that most are highly basic, with pIs >11.5. This unusual chemistry reflects a striking overabundance of arginine residues and occurs despite a relative paucity of lysines. Exogenous expression of the 10 largest eORFs revealed that they accumulate stably in cells as full-length proteins, and most localize to the nucleus and associate with chromatin. Identification of interacting proteins by MS suggested possible roles for these proteins in several nuclear processes. The eORFs studied are well conserved among primates, though they are largely absent from other mammals. Notably, several contain human-specific C-terminal extensions and display properties suggestive of de novo gene birth. In summary, we have discovered that a fraction of human eRNAs can function as mRNAs, revealing a new and unexpected role for these transcripts.
{"title":"Multiple human enhancer RNAs contain long translated open reading frames","authors":"Pavel A. Vlasov, Koichi Ogami, Elizabeth Valenzuela, Risa Karakida Kawaguchi, Marko Jovanovic, James L. Manley","doi":"10.1101/gad.352944.125","DOIUrl":"https://doi.org/10.1101/gad.352944.125","url":null,"abstract":"Enhancer RNAs (eRNAs) are transcribed by <em>RNA polymerase II</em>during enhancer activation but are typically rapidly degraded in the nucleus. During states of reduced RNA surveillance, however, eRNAs and other similar “noncoding” RNAs (including, e.g., upstream antisense RNAs) are stabilized, and some are exported to the cytoplasm and can even be found on polysomes. Here, we report unexpectedly that ∼12% of human intergenic eRNAs contain long open reading frames (>300 nt), many of which can be actively translated, as determined by ribosome profiling, and produce proteins that accumulate in cells, as shown by mass spectrometry (MS) data. Focusing on the largest of the encoded proteins, which we designated as eORFs, which can be up to ∼45 kDa, we found, remarkably, that most are highly basic, with pIs >11.5. This unusual chemistry reflects a striking overabundance of arginine residues and occurs despite a relative paucity of lysines. Exogenous expression of the 10 largest eORFs revealed that they accumulate stably in cells as full-length proteins, and most localize to the nucleus and associate with chromatin. Identification of interacting proteins by MS suggested possible roles for these proteins in several nuclear processes. The eORFs studied are well conserved among primates, though they are largely absent from other mammals. Notably, several contain human-specific C-terminal extensions and display properties suggestive of de novo gene birth. In summary, we have discovered that a fraction of human eRNAs can function as mRNAs, revealing a new and unexpected role for these transcripts.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"31 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031925","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}
Mariano F. Zacarías-Fluck, Daniel Massó-Vallés, Fabio Giuntini, Íñigo González-Larreategui, Jastrinjan Kaur, Sílvia Casacuberta-Serra, Toni Jauset, Sandra Martínez-Martín, Génesis Martín-Fernández, Erika Serrano del Pozo, Laia Foradada, Judit Grueso, Lara Nonell, Marie-Eve Beaulieu, Jonathan R. Whitfield, Laura Soucek
Genes & Development 37: 303–320 (2023)
基因与发育37:303-320 （2023）
{"title":"Corrigendum: Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma","authors":"Mariano F. Zacarías-Fluck, Daniel Massó-Vallés, Fabio Giuntini, Íñigo González-Larreategui, Jastrinjan Kaur, Sílvia Casacuberta-Serra, Toni Jauset, Sandra Martínez-Martín, Génesis Martín-Fernández, Erika Serrano del Pozo, Laia Foradada, Judit Grueso, Lara Nonell, Marie-Eve Beaulieu, Jonathan R. Whitfield, Laura Soucek","doi":"10.1101/gad.352999.125","DOIUrl":"https://doi.org/10.1101/gad.352999.125","url":null,"abstract":"<strong>Genes & Development 37:</strong> 303–320 (2023)","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"29 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930459","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}
Azusa Inoue, Zhiyuan Chen, Qiangzong Yin, Yi Zhang
Genes & Development 32: 1525–1536 (2018)
基因与发育32:1525-1536 （2018）
{"title":"Corrigendum: Maternal Eed knockout causes loss of H3K27me3 imprinting and random X inactivation in the extraembryonic cells","authors":"Azusa Inoue, Zhiyuan Chen, Qiangzong Yin, Yi Zhang","doi":"10.1101/gad.353016.125","DOIUrl":"https://doi.org/10.1101/gad.353016.125","url":null,"abstract":"<strong>Genes & Development 32:</strong> 1525–1536 (2018)","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"11 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930458","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}
Jonathon M. Muncie-Vasic, Tanvi Sinha, Alexander P. Clark, Emily F. Brower, Jeffrey J. Saucerman, Brian L. Black, Benoit G. Bruneau
The gene regulatory networks (GRNs) that control early heart formation are beginning to be understood, but lineage-specific GRNs remain largely undefined. We investigated networks controlled by the vital transcription factor MEF2C using a time course of single-nucleus RNA sequencing and ATAC sequencing in wild-type and Mef2c-null embryos. We identified a “posteriorized” cardiac gene signature and chromatin landscape in the absence of MEF2C. Integrating our multiomics data in a deep learning-based model, we constructed developmental trajectories for each of the outflow tract, ventricular, and inflow tract segments and alterations of these in Mef2c-null embryos. We computationally identified segment-specific MEF2C-dependent enhancers with activity in the developing zebrafish heart. Finally, using inferred GRNs, we discovered that the Mef2c-null heart malformations are partly driven by increased activity of the nuclear hormone receptor NR2F2. Our results delineate lineage-specific GRNs in the early heart tube and provide a generalizable framework for dissecting transcriptional networks governing developmental processes.
{"title":"MEF2C controls segment-specific gene regulatory networks that direct heart tube morphogenesis","authors":"Jonathon M. Muncie-Vasic, Tanvi Sinha, Alexander P. Clark, Emily F. Brower, Jeffrey J. Saucerman, Brian L. Black, Benoit G. Bruneau","doi":"10.1101/gad.352889.125","DOIUrl":"https://doi.org/10.1101/gad.352889.125","url":null,"abstract":"The gene regulatory networks (GRNs) that control early heart formation are beginning to be understood, but lineage-specific GRNs remain largely undefined. We investigated networks controlled by the vital transcription factor MEF2C using a time course of single-nucleus RNA sequencing and ATAC sequencing in wild-type and <em>Mef2c</em>-null embryos. We identified a “posteriorized” cardiac gene signature and chromatin landscape in the absence of MEF2C. Integrating our multiomics data in a deep learning-based model, we constructed developmental trajectories for each of the outflow tract, ventricular, and inflow tract segments and alterations of these in <em>Mef2c</em>-null embryos. We computationally identified segment-specific MEF2C-dependent enhancers with activity in the developing zebrafish heart. Finally, using inferred GRNs, we discovered that the <em>Mef2c</em>-null heart malformations are partly driven by increased activity of the nuclear hormone receptor NR2F2. Our results delineate lineage-specific GRNs in the early heart tube and provide a generalizable framework for dissecting transcriptional networks governing developmental processes.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"23 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915581","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}
Polyadenylation of mRNA is a key step in post-transcriptional regulation. In this issue of Genes & Development, Gabs and colleagues (doi:10.1101/gad.352912.125) provide evidence for a novel, kinetically driven mechanism that dictates the length of poly(A) tails added to mRNAs in budding yeast. The investigators introduce the concept of Nab2, a zinc finger poly(A) RNA binding protein, as a “kinetic ruler,” which functions through dynamic competition with the cleavage and polyadenylation complex (CPAC) to define the length of poly(A) tails.
{"title":"End of the line: a kinetic ruler model for poly(A) tail termination","authors":"Anita H. Corbett","doi":"10.1101/gad.353241.125","DOIUrl":"https://doi.org/10.1101/gad.353241.125","url":null,"abstract":"Polyadenylation of mRNA is a key step in post-transcriptional regulation. In this issue of <em>Genes & Development</em>, Gabs and colleagues (doi:10.1101/gad.352912.125) provide evidence for a novel, kinetically driven mechanism that dictates the length of poly(A) tails added to mRNAs in budding yeast. The investigators introduce the concept of Nab2, a zinc finger poly(A) RNA binding protein, as a “kinetic ruler,” which functions through dynamic competition with the cleavage and polyadenylation complex (CPAC) to define the length of poly(A) tails.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"52 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905913","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}
Constantine Bartolutti, Allison J. Kim, Yanzhe Ma, Thiago P. Fernandes, Charles Boone, Marko Jovanovic, Gloria A. Brar
The unfolded protein response (UPR) was discovered in budding yeast as a mechanism that allows cells to adapt to endoplasmic reticulum (ER) stressors. Although the UPR is not thought to be necessary for cellular fitness of wild-type cells in the absence of stress, we found that UPR deficiency led to poor growth in cycling mitotic yeast cells. This led to pervasive adaptive aneuploidy of specific chromosomes that was seen in divergent strain backgrounds, indicating an important basal role for this pathway that was missed by studies of the most common laboratory-derived strains. Aneuploid UPR-deficient cells grew better than euploid UPR-deficient cells but exhibited heightened general proteostatic stress, a hallmark of aneuploidy in wild-type cells. Modulation of key genes involved in ER proteostasis that were encoded on aneuploid chromosomes could phenocopy the effects of aneuploidy, indicating that the reason UPR-deficient cells become aneuploid is to counteract protein folding stress in the ER. Proteomic analyses indicate that expression of a small subset of stress-induced UPR targets is supported by basal UPR activity, including the chaperone Kar2/BiP. Together, our results reveal an unexpected role for the UPR in baseline ER folding that is important enough to safeguard cellular fitness that cells tolerate the substantial proteostatic costs that result from aneuploidy to counteract its loss.
{"title":"UPR deficiency leads to poor growth, aneuploidy, and a trade-off between ER and general proteostasis in yeast","authors":"Constantine Bartolutti, Allison J. Kim, Yanzhe Ma, Thiago P. Fernandes, Charles Boone, Marko Jovanovic, Gloria A. Brar","doi":"10.1101/gad.352490.124","DOIUrl":"https://doi.org/10.1101/gad.352490.124","url":null,"abstract":"The unfolded protein response (UPR) was discovered in budding yeast as a mechanism that allows cells to adapt to endoplasmic reticulum (ER) stressors. Although the UPR is not thought to be necessary for cellular fitness of wild-type cells in the absence of stress, we found that UPR deficiency led to poor growth in cycling mitotic yeast cells. This led to pervasive adaptive aneuploidy of specific chromosomes that was seen in divergent strain backgrounds, indicating an important basal role for this pathway that was missed by studies of the most common laboratory-derived strains. Aneuploid UPR-deficient cells grew better than euploid UPR-deficient cells but exhibited heightened general proteostatic stress, a hallmark of aneuploidy in wild-type cells. Modulation of key genes involved in ER proteostasis that were encoded on aneuploid chromosomes could phenocopy the effects of aneuploidy, indicating that the reason UPR-deficient cells become aneuploid is to counteract protein folding stress in the ER. Proteomic analyses indicate that expression of a small subset of stress-induced UPR targets is supported by basal UPR activity, including the chaperone Kar2/BiP. Together, our results reveal an unexpected role for the UPR in baseline ER folding that is important enough to safeguard cellular fitness that cells tolerate the substantial proteostatic costs that result from aneuploidy to counteract its loss.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"17 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898386","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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