Emilie Gabs, Emil Aalto-Setälä, Aada Välisaari, Anssi M. Malinen, Torben Heick Jensen, Stephen H. McLaughlin, Lori A. Passmore, Matti Turtola
Poly(A) tails of newly synthesized mRNAs have uniform lengths, arising through cooperation between the cleavage and polyadenylation complex (CPAC) and poly(A) binding proteins (PABPs). In the budding yeast Saccharomyces cerevisiae, the responsible PABP is the evolutionarily conserved CCCH zinc finger protein Nab2 that facilitates the biogenesis of ∼60 adenosine mRNA poly(A) tails. Here, we address the molecular basis for such length control. Reconstituting polyadenylation reactions during the formation of Nab2:poly(A) RNA ribonucleoprotein particles in vitro, we found that Nab2 dimerization directs polyadenylation termination. The Nab2 dimer is stable only on poly(A) tails that are >25 adenosines, explaining how Nab2 avoids prematurely terminating poly(A) synthesis. However, the mature tail length is not determined by the footprint of Nab2 on the RNA but rather by the kinetic competition between CPAC-mediated tail elongation and Nab2 RNA binding. Variations in Nab2 RNA binding rate can shift poly(A) tail lengths, but in cells such variations are buffered by autoregulation of Nab2 protein concentration. As a result, poly(A) tail length control operates through a “kinetic ruler” mechanism, whereby the concentration of Nab2 quantifies RNA length.
{"title":"A kinetic ruler controls mRNA poly(A) tail length","authors":"Emilie Gabs, Emil Aalto-Setälä, Aada Välisaari, Anssi M. Malinen, Torben Heick Jensen, Stephen H. McLaughlin, Lori A. Passmore, Matti Turtola","doi":"10.1101/gad.352912.125","DOIUrl":"https://doi.org/10.1101/gad.352912.125","url":null,"abstract":"Poly(A) tails of newly synthesized mRNAs have uniform lengths, arising through cooperation between the cleavage and polyadenylation complex (CPAC) and poly(A) binding proteins (PABPs). In the budding yeast <em>Saccharomyces cerevisiae</em>, the responsible PABP is the evolutionarily conserved CCCH zinc finger protein Nab2 that facilitates the biogenesis of ∼60 adenosine mRNA poly(A) tails. Here, we address the molecular basis for such length control. Reconstituting polyadenylation reactions during the formation of Nab2:poly(A) RNA ribonucleoprotein particles in vitro, we found that Nab2 dimerization directs polyadenylation termination. The Nab2 dimer is stable only on poly(A) tails that are >25 adenosines, explaining how Nab2 avoids prematurely terminating poly(A) synthesis. However, the mature tail length is not determined by the footprint of Nab2 on the RNA but rather by the kinetic competition between CPAC-mediated tail elongation and Nab2 RNA binding. Variations in Nab2 RNA binding rate can shift poly(A) tail lengths, but in cells such variations are buffered by autoregulation of Nab2 protein concentration. As a result, poly(A) tail length control operates through a “kinetic ruler” mechanism, whereby the concentration of Nab2 quantifies RNA length.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"43 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898432","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}
Sushanta Kumar Mishra, Bo Li, Ana S.H. Costa, Linda Van Aelst, Lingbo Zhang
Vitamin B6 is a metabolic cofactor that underpins critical regulatory pathways, including amino acid flux, one-carbon pathways, redox homeostasis, and neurotransmitter biosynthesis. Emerging evidence suggests that vitamin B6 deficiency or its metabolic dysregulation perturbs these core metabolic pathways, driving oncogenic programs in both solid tumors and hematologic malignancies. Moreover, vitamin B6-dependent processes can modulate several tumorigenic processes, such as proliferation, oncogenic signaling, immune regulation, and adaptive metabolic reprogramming. The tumor-specific spatiotemporal dynamics of vitamin B6 metabolism uncover context-dependent metabolic vulnerabilities that are tightly regulated by cellular state and tumor niche. This review addresses emerging mechanistic insights into the multifaceted functions of vitamin B6 in tumorigenesis. Furthermore, it proposes dynamic vitamin B6 metabolism as a promising therapeutic axis, offering novel opportunities for tumor-specific targeted intervention.
{"title":"Multifaceted role of the vitamin B6 pathway in cancer: metabolism, immune interaction, and temporal and spatial regulation","authors":"Sushanta Kumar Mishra, Bo Li, Ana S.H. Costa, Linda Van Aelst, Lingbo Zhang","doi":"10.1101/gad.352770.125","DOIUrl":"https://doi.org/10.1101/gad.352770.125","url":null,"abstract":"Vitamin B6 is a metabolic cofactor that underpins critical regulatory pathways, including amino acid flux, one-carbon pathways, redox homeostasis, and neurotransmitter biosynthesis. Emerging evidence suggests that vitamin B6 deficiency or its metabolic dysregulation perturbs these core metabolic pathways, driving oncogenic programs in both solid tumors and hematologic malignancies. Moreover, vitamin B6-dependent processes can modulate several tumorigenic processes, such as proliferation, oncogenic signaling, immune regulation, and adaptive metabolic reprogramming. The tumor-specific spatiotemporal dynamics of vitamin B6 metabolism uncover context-dependent metabolic vulnerabilities that are tightly regulated by cellular state and tumor niche. This review addresses emerging mechanistic insights into the multifaceted functions of vitamin B6 in tumorigenesis. Furthermore, it proposes dynamic vitamin B6 metabolism as a promising therapeutic axis, offering novel opportunities for tumor-specific targeted intervention.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"9 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898387","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}
Growing disparities in treatment outcomes for acute myeloid leukemia (AML) call for particular attention to features of the disease that vary among populations. In this issue of Genes & Development, Pawar and colleagues (doi:10.1101/gad.352602.125) now reveal that mutations in PHIP, more prevalent among Black patients with AML, disrupt the function of the chromatin regulator PHF6. They corroborate that the latter protein represses gene transcription upon binding open and active regions of chromatin and show that PHF6 missense mutations observed in AML result in loss of function. These insights advance our understanding of disease pathogenesis and may inform efforts to address racial disparities in treatment.
{"title":"A new link in the leukemia genetic puzzle","authors":"Xiaodi Wu, Ross L. Levine","doi":"10.1101/gad.353189.125","DOIUrl":"https://doi.org/10.1101/gad.353189.125","url":null,"abstract":"Growing disparities in treatment outcomes for acute myeloid leukemia (AML) call for particular attention to features of the disease that vary among populations. In this issue of <em>Genes & Development</em>, Pawar and colleagues (doi:10.1101/gad.352602.125) now reveal that mutations in <em>PHIP</em>, more prevalent among Black patients with AML, disrupt the function of the chromatin regulator PHF6. They corroborate that the latter protein represses gene transcription upon binding open and active regions of chromatin and show that <em>PHF6</em> missense mutations observed in AML result in loss of function. These insights advance our understanding of disease pathogenesis and may inform efforts to address racial disparities in treatment.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"20 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144824981","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}
Neuza R. Matias, Lorenzo Gallicchio, Dan Lu, Jongmin J. Kim, Julian Perez, Angela M. Detweiler, Chenggang Lu, Benjamin Bolival, Margaret T. Fuller
Regulators of chromatin accessibility play key roles in cell fate transitions, triggering the onset of novel transcription programs as cells differentiate. In the Drosophila male germline stem cell lineage, tMAC, a master regulator of spermatocyte differentiation that binds thousands of loci, is required for local opening of chromatin, allowing activation of spermatocyte-specific promoters. Here we show that a cell type-specific surveillance system involving the multiple zinc finger protein Kmg and the pipsqueak domain protein Dany dampens transcriptional output from weak tMAC-dependent promoters and counteracts tMAC binding at thousands of additional cryptic promoters, thus preventing massive expression of aberrant protein-coding transcripts. ChIP-seq showed Kmg enriched at the tMAC-bound promoters that it repressed, consistent with direct action. In contrast, Kmg and Dany did not repress highly expressed tMAC-dependent genes, where they colocalized with their binding partner, the chromatin remodeler Mi-2 (NuRD), along the transcribed regions rather than at the promoter. We discuss a model where Kmg, together with Dany and Mi-2, dampens expression from weak or ectopic promoters while allowing robust transcription from highly expressed Aly-dependent genes.
{"title":"A cell type-specific surveillance complex represses cryptic promoters during differentiation in an adult stem cell lineage","authors":"Neuza R. Matias, Lorenzo Gallicchio, Dan Lu, Jongmin J. Kim, Julian Perez, Angela M. Detweiler, Chenggang Lu, Benjamin Bolival, Margaret T. Fuller","doi":"10.1101/gad.352747.125","DOIUrl":"https://doi.org/10.1101/gad.352747.125","url":null,"abstract":"Regulators of chromatin accessibility play key roles in cell fate transitions, triggering the onset of novel transcription programs as cells differentiate. In the <em>Drosophila</em> male germline stem cell lineage, tMAC, a master regulator of spermatocyte differentiation that binds thousands of loci, is required for local opening of chromatin, allowing activation of spermatocyte-specific promoters. Here we show that a cell type-specific surveillance system involving the multiple zinc finger protein Kmg and the pipsqueak domain protein Dany dampens transcriptional output from weak tMAC-dependent promoters and counteracts tMAC binding at thousands of additional cryptic promoters, thus preventing massive expression of aberrant protein-coding transcripts. ChIP-seq showed Kmg enriched at the tMAC-bound promoters that it repressed, consistent with direct action. In contrast, Kmg and Dany did not repress highly expressed tMAC-dependent genes, where they colocalized with their binding partner, the chromatin remodeler Mi-2 (NuRD), along the transcribed regions rather than at the promoter. We discuss a model where Kmg, together with Dany and Mi-2, dampens expression from weak or ectopic promoters while allowing robust transcription from highly expressed Aly-dependent genes.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"1 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792301","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}
Chiara Nicoletti, Jimmy Massenet, Andreas P. Pintado-Urbanc, Leah J. Connor, Monica Nicolau, Swetha Sundar, Mingzhi Xu, Anthony Schmitt, Wenxin Zhang, Zesen Fang, Tsz Ching Indigo Chan, Yu Xin Wang, Stephen J. Tapscott, Tom H. Cheung, Matthew D. Simon, Luca Caputo, Pier Lorenzo Puri
We report here on the identification of a previously unrecognized property of MYOD as a repressor of gene expression via E-box-independent chromatin binding during the process of somatic cell trans-differentiation into skeletal muscle. When ectopically expressed in proliferating human fibroblasts or endogenously induced in activated muscle stem cells (MuSCs), MYOD was detected at accessible regulatory elements of expressed genes, invariably leading to reduced chromatin accessibility and gene repression. At variance with conventional E-box-driven increased chromatin accessibility and H3K27 acetylation at previously silent loci of MYOD-activated genes, MYOD-mediated chromatin compaction and repression of transcription was associated with high occurrence of non-E-box motifs and did not lead to reduced levels of H3K27ac but coincided with reduced levels of H4 acetyl-methyl lysine modification (Kacme). Using MYOD mutants, we dissected the molecular mechanism of MYOD-mediated repression, whereby repression of mitogen-responsive and growth factor-responsive genes occurred via promoter binding, which requires a conserved domain within the first helix; conversely, repression of cell of origin/alternative lineage genes occurred via binding and decommissioning of distal regulatory elements such as superenhancers (SEs), required either the N-terminal activation domain or the two chromatin remodeling domains, and coincided with reduced strength of CTCF-mediated chromatin interactions. These data extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator. They also reveal an unprecedented functional versatility arising from alternative chromatin recruitment through E-box or non-E-box sequences, whereby genetic determinants dictate differential usage of MYOD functional domains.
{"title":"MYOD represses gene expression from non-E-box motifs","authors":"Chiara Nicoletti, Jimmy Massenet, Andreas P. Pintado-Urbanc, Leah J. Connor, Monica Nicolau, Swetha Sundar, Mingzhi Xu, Anthony Schmitt, Wenxin Zhang, Zesen Fang, Tsz Ching Indigo Chan, Yu Xin Wang, Stephen J. Tapscott, Tom H. Cheung, Matthew D. Simon, Luca Caputo, Pier Lorenzo Puri","doi":"10.1101/gad.352708.125","DOIUrl":"https://doi.org/10.1101/gad.352708.125","url":null,"abstract":"We report here on the identification of a previously unrecognized property of MYOD as a repressor of gene expression via E-box-independent chromatin binding during the process of somatic cell <em>trans</em>-differentiation into skeletal muscle. When ectopically expressed in proliferating human fibroblasts or endogenously induced in activated muscle stem cells (MuSCs), MYOD was detected at accessible regulatory elements of expressed genes, invariably leading to reduced chromatin accessibility and gene repression. At variance with conventional E-box-driven increased chromatin accessibility and H3K27 acetylation at previously silent loci of MYOD-activated genes, MYOD-mediated chromatin compaction and repression of transcription was associated with high occurrence of non-E-box motifs and did not lead to reduced levels of H3K27ac but coincided with reduced levels of H4 acetyl-methyl lysine modification (Kacme). Using MYOD mutants, we dissected the molecular mechanism of MYOD-mediated repression, whereby repression of mitogen-responsive and growth factor-responsive genes occurred via promoter binding, which requires a conserved domain within the first helix; conversely, repression of cell of origin/alternative lineage genes occurred via binding and decommissioning of distal regulatory elements such as superenhancers (SEs), required either the N-terminal activation domain or the two chromatin remodeling domains, and coincided with reduced strength of CTCF-mediated chromatin interactions. These data extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator. They also reveal an unprecedented functional versatility arising from alternative chromatin recruitment through E-box or non-E-box sequences, whereby genetic determinants dictate differential usage of MYOD functional domains.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"732 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792318","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}
We are perhaps the only species that realizes our own mortality. We see the path to our eventual demise through the process of aging. This knowledge has shaped our cultures, religions, art, and philosophy, as well as our pursuit to understand aging in the hopes of delaying it. For decades, scientists have formulated theories about aging to make hypotheses that could be tested in the laboratory. The biology of aging is one of the most complex processes that exist and is often thought to be intractable. Over the past four decades, considerable advances in the field of aging research have brought …
{"title":"Aging is growing up: celebrating the latest research in aging and senescence biology","authors":"Andrew Dillin","doi":"10.1101/gad.353136.125","DOIUrl":"https://doi.org/10.1101/gad.353136.125","url":null,"abstract":"We are perhaps the only species that realizes our own mortality. We see the path to our eventual demise through the process of aging. This knowledge has shaped our cultures, religions, art, and philosophy, as well as our pursuit to understand aging in the hopes of delaying it. For decades, scientists have formulated theories about aging to make hypotheses that could be tested in the laboratory. The biology of aging is one of the most complex processes that exist and is often thought to be intractable. Over the past four decades, considerable advances in the field of aging research have brought …","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"719 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755809","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}
Aishwarya S. Pawar, Patrick Somers, Aleena Alex, Jason Grana, Victoria K. Feist, Subin S. George, Sapana S. Jalnapurkar, Charles Antony, Roman Verner, Sanese K. White-Brown, Mohit Khera, María Saraí Mendoza-Figueroa, Kathy Fange Liu, Jennifer J.D. Morrissette, Sandeep Gurbuxani, Vikram R. Paralkar
Myeloid leukemias are heterogeneous cancers with diverse mutations, sometimes in genes with unclear roles and unknown functional partners. PHF6 and PHIP are two poorly understood chromatin-binding proteins recurrently mutated in acute myeloid leukemia (AML). PHF6 mutations are associated with poorer outcomes, whereas PHIP was recently identified as the most common selective mutation in Black patients with AML. Here, we show that Phf6 knockout converts Flt3-ITD-driven mouse chronic myelomonocytic leukemia (CMML) into AML with reduced survival. Using cell line models, we show that PHF6 is a transcriptional repressor that suppresses a limited stemness gene network and that PHF6 missense mutations, classified by current clinical algorithms as variants of unknown significance, produce unstable or nonfunctional protein. We present multiple lines of evidence converging on a critical mechanistic connection between PHF6 and PHIP. We show that PHIP loss phenocopies PHF6 loss and that PHF6 requires PHIP to occupy chromatin and exert its downstream transcriptional program. Our work unifies PHF6 and PHIP, two disparate leukemia mutated proteins, into a common functional complex that suppresses AML stemness.
{"title":"Leukemia mutated proteins PHF6 and PHIP form a chromatin complex that represses acute myeloid leukemia stemness","authors":"Aishwarya S. Pawar, Patrick Somers, Aleena Alex, Jason Grana, Victoria K. Feist, Subin S. George, Sapana S. Jalnapurkar, Charles Antony, Roman Verner, Sanese K. White-Brown, Mohit Khera, María Saraí Mendoza-Figueroa, Kathy Fange Liu, Jennifer J.D. Morrissette, Sandeep Gurbuxani, Vikram R. Paralkar","doi":"10.1101/gad.352602.125","DOIUrl":"https://doi.org/10.1101/gad.352602.125","url":null,"abstract":"Myeloid leukemias are heterogeneous cancers with diverse mutations, sometimes in genes with unclear roles and unknown functional partners. PHF6 and PHIP are two poorly understood chromatin-binding proteins recurrently mutated in acute myeloid leukemia (AML). <em>PHF6</em> mutations are associated with poorer outcomes, whereas <em>PHIP</em> was recently identified as the most common selective mutation in Black patients with AML. Here, we show that <em>Phf6</em> knockout converts <em>Flt3-ITD</em>-driven mouse chronic myelomonocytic leukemia (CMML) into AML with reduced survival. Using cell line models, we show that PHF6 is a transcriptional repressor that suppresses a limited stemness gene network and that <em>PHF6</em> missense mutations, classified by current clinical algorithms as variants of unknown significance, produce unstable or nonfunctional protein. We present multiple lines of evidence converging on a critical mechanistic connection between PHF6 and PHIP. We show that <em>PHIP</em> loss phenocopies <em>PHF6</em> loss and that PHF6 requires PHIP to occupy chromatin and exert its downstream transcriptional program. Our work unifies PHF6 and PHIP, two disparate leukemia mutated proteins, into a common functional complex that suppresses AML stemness.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"62 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719698","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}
Throughout the last century, aneuploidy has been cemented as a hallmark of cancer. Although the association of aneuploidy with tumorigenesis has been well established, the role of these genetic imbalances in tumor formation has only recently begun to be elucidated. Advancements in genomics have revealed the complexity and context dependence of the effect of aneuploidy on cancer growth, while developments in genetic editing have allowed for proper modeling of specific aneuploidies. In this review, we discuss the key factors to consider when studying the role of aneuploidy in cancer and the tools that are available to do so. We then highlight recent studies that establish phenotypic contributions of aneuploidy to tumorigenicity. In particular, we highlight how general aneuploidy and chromosomal instability affect the tumor microenvironment and how specific chromosomal alterations, including the loss of chromosome 9p and the gain of chromosomes 8q and 1q, influence tumor behavior and therapeutic responses. Finally, we emphasize the potential of targeting aneuploidy-induced vulnerabilities to improve cancer treatment outcomes.
{"title":"Modeling and targeting general and chromosome-specific aneuploidy in cancer","authors":"Aleah Goldberg, Maria Trifas, Teresa Davoli","doi":"10.1101/gad.352766.125","DOIUrl":"https://doi.org/10.1101/gad.352766.125","url":null,"abstract":"Throughout the last century, aneuploidy has been cemented as a hallmark of cancer. Although the association of aneuploidy with tumorigenesis has been well established, the role of these genetic imbalances in tumor formation has only recently begun to be elucidated. Advancements in genomics have revealed the complexity and context dependence of the effect of aneuploidy on cancer growth, while developments in genetic editing have allowed for proper modeling of specific aneuploidies. In this review, we discuss the key factors to consider when studying the role of aneuploidy in cancer and the tools that are available to do so. We then highlight recent studies that establish phenotypic contributions of aneuploidy to tumorigenicity. In particular, we highlight how general aneuploidy and chromosomal instability affect the tumor microenvironment and how specific chromosomal alterations, including the loss of chromosome 9p and the gain of chromosomes 8q and 1q, influence tumor behavior and therapeutic responses. Finally, we emphasize the potential of targeting aneuploidy-induced vulnerabilities to improve cancer treatment outcomes.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"90 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719700","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}
Jaime Alegrio-Louro, Grisel Cruz-Becerra, George A. Kassavetis, James T. Kadonaga, Andres E. Leschziner
The tardigrade damage suppressor (Dsup) and vertebrate high-mobility group N (HMGN) proteins bind specifically to nucleosomes via a conserved motif whose structure has not been experimentally determined. Here we used cryo-EM to show that both proteins bind to the nucleosome acidic patch via analogous arginine anchors with one molecule bound to each face of the nucleosome. We additionally used the natural promoter-containing 5S rDNA sequence for structural analysis of the nucleosome. These structures of an ancient nucleosome-binding motif suggest that there is an untapped realm of proteins with a related mode of binding to chromatin.
{"title":"Structural basis of nucleosome recognition by the conserved Dsup and HMGN nucleosome-binding motif","authors":"Jaime Alegrio-Louro, Grisel Cruz-Becerra, George A. Kassavetis, James T. Kadonaga, Andres E. Leschziner","doi":"10.1101/gad.352720.125","DOIUrl":"https://doi.org/10.1101/gad.352720.125","url":null,"abstract":"The tardigrade damage suppressor (Dsup) and vertebrate high-mobility group N (HMGN) proteins bind specifically to nucleosomes via a conserved motif whose structure has not been experimentally determined. Here we used cryo-EM to show that both proteins bind to the nucleosome acidic patch via analogous arginine anchors with one molecule bound to each face of the nucleosome. We additionally used the natural promoter-containing 5S rDNA sequence for structural analysis of the nucleosome. These structures of an ancient nucleosome-binding motif suggest that there is an untapped realm of proteins with a related mode of binding to chromatin.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"12 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719699","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}
Lineage plasticity drives treatment resistance in lung adenocarcinoma (LUAD) as cancer cells adopt new identities. In this issue of Genes & Development, Fort and colleagues (doi:10.1101/gad.352742.125) report HNF4α as a key regulator of hybrid identity states and tumor progression in NKX2-1-positive LUAD. Using murine and human models, they show that HNF4α promotes gastrointestinal/liver-like programs and suppresses pulmonary identity by modulating cell identity-specific binding of NKX2-1. In addition, RAS/MEK signaling was implicated in maintenance of this hybrid identity state by regulating NKX2-1 chromatin binding in LUAD. These findings nominate HNF4α as a driver of LUAD plasticity and a potential therapeutic target to overcome resistance.
{"title":"Lineage rewiring in lung adenocarcinoma via HNF4α and NKX2-1 dynamics","authors":"Alice Feng, Alena Yermalovich, Matthew Meyerson","doi":"10.1101/gad.353142.125","DOIUrl":"https://doi.org/10.1101/gad.353142.125","url":null,"abstract":"Lineage plasticity drives treatment resistance in lung adenocarcinoma (LUAD) as cancer cells adopt new identities. In this issue of <em>Genes & Development</em>, Fort and colleagues (doi:10.1101/gad.352742.125) report HNF4α as a key regulator of hybrid identity states and tumor progression in NKX2-1-positive LUAD. Using murine and human models, they show that HNF4α promotes gastrointestinal/liver-like programs and suppresses pulmonary identity by modulating cell identity-specific binding of NKX2-1. In addition, RAS/MEK signaling was implicated in maintenance of this hybrid identity state by regulating NKX2-1 chromatin binding in LUAD. These findings nominate HNF4α as a driver of LUAD plasticity and a potential therapeutic target to overcome resistance.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"33 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701925","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：