RESUMO
Contrary to multicellular organisms that display segmentation during development, communities of unicellular organisms are believed to be devoid of such sophisticated patterning. Unexpectedly, we find that the gene expression underlying the nitrogen stress response of a developing Bacillus subtilis biofilm becomes organized into a ring-like pattern. Mathematical modeling and genetic probing of the underlying circuit indicate that this patterning is generated by a clock and wavefront mechanism, similar to that driving vertebrate somitogenesis. We experimentally validated this hypothesis by showing that predicted nutrient conditions can even lead to multiple concentric rings, resembling segments. We additionally confirmed that this patterning mechanism is driven by cell-autonomous oscillations. Importantly, we show that the clock and wavefront process also spatially patterns sporulation within the biofilm. Together, these findings reveal a biofilm segmentation clock that organizes cellular differentiation in space and time, thereby challenging the paradigm that such patterning mechanisms are exclusive to plant and animal development.
Assuntos
Bacillus subtilis/crescimento & desenvolvimento , Bacillus subtilis/genética , Biofilmes/crescimento & desenvolvimento , Padronização Corporal/genética , Bacillus subtilis/metabolismo , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Cinética , Modelos Biológicos , Nitrogênio/metabolismo , Transdução de Sinais/genética , Somitos/crescimento & desenvolvimento , Esporos Bacterianos/crescimento & desenvolvimento , Estresse Fisiológico/genética , Fatores de TempoRESUMO
The human gut microbiota resides within a diverse chemical environment challenging our ability to understand the forces shaping this ecosystem. Here, we reveal that fitness of the Bacteroidales, the dominant order of bacteria in the human gut, is an emergent property of glycans and one specific metabolite, butyrate. Distinct sugars serve as strain-variable fitness switches activating context-dependent inhibitory functions of butyrate. Differential fitness effects of butyrate within the Bacteroides are mediated by species-level variation in Acyl-CoA thioesterase activity and nucleotide polymorphisms regulating an Acyl-CoA transferase. Using in vivo multi-omic profiles, we demonstrate Bacteroides fitness in the human gut is associated together, but not independently, with Acyl-CoA transferase expression and butyrate. Our data reveal that each strain of the Bacteroides exists within a unique fitness landscape based on the interaction of chemical components unpredictable by the effect of each part alone mediated by flexibility in the core genome.
Assuntos
Microbioma Gastrointestinal , Metaboloma , Polissacarídeos/metabolismo , Acil Coenzima A/metabolismo , Sequência de Aminoácidos , Aminoácidos de Cadeia Ramificada/metabolismo , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/genética , Bacteroidetes/crescimento & desenvolvimento , Butiratos/química , Butiratos/farmacologia , Coenzima A-Transferases/química , Coenzima A-Transferases/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Variação Genética/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Metaboloma/efeitos dos fármacos , Metaboloma/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Especificidade da Espécie , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Transcrição Gênica/efeitos dos fármacosRESUMO
CRISPR-Cas systems provide prokaryotes with acquired immunity against viruses and plasmids, but how these systems are regulated to prevent autoimmunity is poorly understood. Here, we show that in the S. pyogenes CRISPR-Cas system, a long-form transactivating CRISPR RNA (tracr-L) folds into a natural single guide that directs Cas9 to transcriptionally repress its own promoter (Pcas). Further, we demonstrate that Pcas serves as a critical regulatory node. De-repression causes a dramatic 3,000-fold increase in immunization rates against viruses; however, heightened immunity comes at the cost of increased autoimmune toxicity. Using bioinformatic analyses, we provide evidence that tracrRNA-mediated autoregulation is widespread in type II-A CRISPR-Cas systems. Collectively, we unveil a new paradigm for the intrinsic regulation of CRISPR-Cas systems by natural single guides, which may facilitate the frequent horizontal transfer of these systems into new hosts that have not yet evolved their own regulatory strategies.
Assuntos
Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Expressão Gênica , Homeostase/genética , RNA Guia de Cinetoplastídeos/genética , Autoimunidade/genética , Sequência de Bases , Sequência Conservada , Regulação para Baixo/genética , Modelos Genéticos , Mutação/genética , Óperon/genética , Regiões Promotoras Genéticas/genética , Streptococcus pyogenes/genética , Estresse Fisiológico/genética , Transcrição Gênica , Ativação Transcricional/genéticaRESUMO
Estrogen receptor α (ERα) is a hormone receptor and key driver for over 70% of breast cancers that has been studied for decades as a transcription factor. Unexpectedly, we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERα RNA binding function is uncoupled from its activity to bind DNA and critical for breast cancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP) sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustain cancer cell fitness and elicit cellular responses to stress. Mechanistically, ERα controls different steps of RNA metabolism. In particular, we demonstrate that ERα RNA binding mediates alternative splicing of XBP1 and translation of the eIF4G2 and MCL1 mRNAs, which facilitates survival upon stress conditions and sustains tamoxifen resistance of cancer cells. ERα is therefore a multifaceted RNA-binding protein, and this activity transforms our knowledge of post-transcriptional regulation underlying cancer development and drug response.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Sequência de Bases , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/química , Fator de Iniciação Eucariótico 4G/genética , Fator de Iniciação Eucariótico 4G/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica , Humanos , Camundongos Endogâmicos NOD , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Oncogenes , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Splicing de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Tamoxifeno/farmacologia , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
Stressed cells shut down translation, release mRNA molecules from polysomes, and form stress granules (SGs) via a network of interactions that involve G3BP. Here we focus on the mechanistic underpinnings of SG assembly. We show that, under non-stress conditions, G3BP adopts a compact auto-inhibited state stabilized by electrostatic intramolecular interactions between the intrinsically disordered acidic tracts and the positively charged arginine-rich region. Upon release from polysomes, unfolded mRNAs outcompete G3BP auto-inhibitory interactions, engendering a conformational transition that facilitates clustering of G3BP through protein-RNA interactions. Subsequent physical crosslinking of G3BP clusters drives RNA molecules into networked RNA/protein condensates. We show that G3BP condensates impede RNA entanglement and recruit additional client proteins that promote SG maturation or induce a liquid-to-solid transition that may underlie disease. We propose that condensation coupled to conformational rearrangements and heterotypic multivalent interactions may be a general principle underlying RNP granule assembly.
Assuntos
Grânulos Citoplasmáticos/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Ribonucleoproteínas/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Citoplasma/metabolismo , Células HeLa , Humanos , Conformação de Ácido Nucleico , Organelas/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Estresse Fisiológico/genéticaRESUMO
In response to biotic stress, plants produce suites of highly modified fatty acids that bear unusual chemical functionalities. Despite their chemical complexity and proposed roles in pathogen defense, little is known about the biosynthesis of decorated fatty acids in plants. Falcarindiol is a prototypical acetylenic lipid present in carrot, tomato, and celery that inhibits growth of fungi and human cancer cell lines. Using a combination of untargeted metabolomics and RNA sequencing, we discovered a biosynthetic gene cluster in tomato (Solanum lycopersicum) required for falcarindiol production. By reconstituting initial biosynthetic steps in a heterologous host and generating transgenic pathway mutants in tomato, we demonstrate a direct role of the cluster in falcarindiol biosynthesis and resistance to fungal and bacterial pathogens in tomato leaves. This work reveals a mechanism by which plants sculpt their lipid pool in response to pathogens and provides critical insight into the complex biochemistry of alkynyl lipid production.
Assuntos
Di-Inos/metabolismo , Ácidos Graxos/biossíntese , Álcoois Graxos/metabolismo , Solanum lycopersicum/genética , Resistência à Doença/genética , Di-Inos/química , Ácidos Graxos/metabolismo , Álcoois Graxos/química , Regulação da Expressão Gênica de Plantas/genética , Metabolômica , Família Multigênica/genética , Doenças das Plantas/microbiologia , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Estresse Fisiológico/genéticaRESUMO
Continuous supply of immune cells throughout life relies on the delicate balance in the hematopoietic stem cell (HSC) pool between long-term maintenance and meeting the demands of both normal blood production and unexpected stress conditions. Here we identified distinct subsets of human long-term (LT)-HSCs that responded differently to regeneration-mediated stress: an immune checkpoint ligand CD112lo subset that exhibited a transient engraftment restraint (termed latency) before contributing to hematopoietic reconstitution and a primed CD112hi subset that responded rapidly. This functional heterogeneity and CD112 expression are regulated by INKA1 through direct interaction with PAK4 and SIRT1, inducing epigenetic changes and defining an alternative state of LT-HSC quiescence that serves to preserve self-renewal and regenerative capacity upon regeneration-mediated stress. Collectively, our data uncovered the molecular intricacies underlying HSC heterogeneity and self-renewal regulation and point to latency as an orchestrated physiological response that balances blood cell demands with preserving a stem cell reservoir.
Assuntos
Autorrenovação Celular/imunologia , Células-Tronco Hematopoéticas/fisiologia , Reconstituição Imune , Células-Tronco Multipotentes/fisiologia , Estresse Fisiológico/imunologia , Adulto , Animais , Autorrenovação Celular/genética , Células Cultivadas , Epigênese Genética/imunologia , Feminino , Sangue Fetal/citologia , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Hematopoese , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Separação Imunomagnética , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Nectinas/metabolismo , Cultura Primária de Células , RNA-Seq , Análise de Célula Única , Sirtuína 1/metabolismo , Estresse Fisiológico/genética , Transplante Heterólogo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismoRESUMO
A large and significant portion of eukaryotic transcriptomes consists of noncoding RNAs (ncRNAs) that have minimal or no protein-coding capacity but are functional. Diverse ncRNAs, including both small RNAs and long ncRNAs (lncRNAs), play essential regulatory roles in almost all biological processes by modulating gene expression at the transcriptional and posttranscriptional levels. In this review, we summarize the current knowledge of plant small RNAs and lncRNAs, with a focus on their biogenesis, modes of action, local and systemic movement, and functions at the nexus of plant development and environmental responses. The complex connections among small RNAs, lncRNAs, and small peptides in plants are also discussed, along with the challenges of identifying and investigating new classes of ncRNAs.
Assuntos
Desenvolvimento Vegetal/genética , Plantas/genética , RNA Longo não Codificante/metabolismo , RNA de Plantas/metabolismo , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , RNA de Plantas/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismoRESUMO
The dual leucine zipper-bearing kinase (DLK) and leucine zipper-bearing kinase (LZK) are evolutionarily conserved MAPKKKs of the mixed-lineage kinase family. Acting upstream of stress-responsive JNK and p38 MAP kinases, DLK and LZK have emerged as central players in neuronal responses to a variety of acute and traumatic injuries. Recent studies also implicate their function in astrocytes, microglia, and other nonneuronal cells, reflecting their expanding roles in the multicellular response to injury and in disease. Of particular note is the potential link of these kinases to neurodegenerative diseases and cancer. It is thus critical to understand the physiological contexts under which these kinases are activated, as well as the signal transduction mechanisms that mediate specific functional outcomes. In this review we first provide a historical overview of the biochemical and functional dissection of these kinases. We then discuss recent findings on regulating their activity to enhance cellular protection following injury and in disease, focusing on but not limited to the nervous system.
Assuntos
Zíper de Leucina/genética , MAP Quinase Quinase Quinases/metabolismo , Neurônios/metabolismo , Estresse Fisiológico/genética , Animais , Axônios/metabolismo , Humanos , MAP Quinase Quinase Quinases/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/virologia , Neuroglia/metabolismo , Neurônios/virologia , Regeneração/genética , Regeneração/fisiologia , Células-Tronco/metabolismo , Estresse Fisiológico/fisiologia , Ferimentos e Lesões/genética , Ferimentos e Lesões/metabolismoRESUMO
As sessile organisms, plants must cope with abiotic stress such as soil salinity, drought, and extreme temperatures. Core stress-signaling pathways involve protein kinases related to the yeast SNF1 and mammalian AMPK, suggesting that stress signaling in plants evolved from energy sensing. Stress signaling regulates proteins critical for ion and water transport and for metabolic and gene-expression reprogramming to bring about ionic and water homeostasis and cellular stability under stress conditions. Understanding stress signaling and responses will increase our ability to improve stress resistance in crops to achieve agricultural sustainability and food security for a growing world population.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Produtos Agrícolas/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Estresse Fisiológico/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Cloroplastos/enzimologia , Resposta ao Choque Frio , Produtos Agrícolas/enzimologia , Produtos Agrícolas/genética , Secas , Estresse do Retículo Endoplasmático , Metabolismo Energético , Abastecimento de Alimentos , Regulação da Expressão Gênica de Plantas , Resposta ao Choque Térmico , Mitocôndrias/enzimologia , Pressão Osmótica , Peroxissomos/enzimologia , Proteínas Serina-Treonina Quinases/genética , Salinidade , Transdução de Sinais , Estresse Fisiológico/genéticaRESUMO
Advances in sequencing and high-throughput techniques have provided an unprecedented opportunity to interrogate human diseases on a genome-wide scale. The list of disease-causing mutations is expanding rapidly, and mutations affecting mRNA translation are no exception. Translation (protein synthesis) is one of the most complex processes in the cell. The orchestrated action of ribosomes, tRNAs and numerous translation factors decodes the information contained in mRNA into a polypeptide chain. The intricate nature of this process renders it susceptible to deregulation at multiple levels. In this Review, we summarize current evidence of translation deregulation in human diseases other than cancer. We discuss translation-related diseases on the basis of the molecular aberration that underpins their pathogenesis (including tRNA dysfunction, ribosomopathies, deregulation of the integrated stress response and deregulation of the mTOR pathway) and describe how deregulation of translation generates the phenotypic variability observed in these disorders.
Assuntos
Doença/genética , Biossíntese de Proteínas/genética , Biossíntese de Proteínas/fisiologia , Animais , Variação Biológica da População/genética , Humanos , Fatores de Iniciação de Peptídeos/genética , RNA Mensageiro/genética , RNA de Transferência/genética , Ribossomos/genética , Estresse Fisiológico/genética , Serina-Treonina Quinases TOR/genéticaRESUMO
Many organisms have developed a robust ability to adapt and survive in the face of environmental perturbations that threaten the integrity of their genome, proteome, or metabolome. Studies in multiple model organisms have shown that, in general, when exposed to stress, cells activate a complex prosurvival signaling network that includes immune and DNA damage response genes, chaperones, antioxidant enzymes, structural proteins, metabolic enzymes, and noncoding RNAs. The manner of activation runs the gamut from transcriptional induction of genes to increased stability of transcripts to posttranslational modification of important biosynthetic proteins within the stressed tissue. Superimposed on these largely autonomous effects are nonautonomous responses in which the stressed tissue secretes peptides and other factors that stimulate tissues in different organs to embark on processes that ultimately help the organism as a whole cope with stress. This review focuses on the mechanisms by which tissues in one organ adapt to environmental challenges by regulating stress responses in tissues of different organs.
Assuntos
Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Animais , Humanos , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/fisiologiaRESUMO
Anniina Vihervaara and Lea Sistonen share with us some of their experiences, including the paths to setting up their own labs and some behind-the-scenes details about their paper, "Stress-induced transcriptional memory accelerates promoter-proximal pause-release and decelerates termination over mitotic divisions."
Assuntos
Transcrição Gênica/genética , Humanos , Pessoal de Laboratório , Mitose/genética , Regiões Promotoras Genéticas/genética , Pesquisa , Estresse Fisiológico/genéticaRESUMO
Temperature is a variable component of the environment, and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses, resulting in refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to reduction of temperature-sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find that many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and, importantly, cellular functions. We postulate that, in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.
Assuntos
Adaptação Fisiológica/genética , Proteoma/genética , Estresse Fisiológico/genética , Transcriptoma/genética , Aclimatação/genética , Animais , Exposição Ambiental/efeitos adversos , Regulação Fúngica da Expressão Gênica/genética , Temperatura Alta/efeitos adversos , Saccharomycetales/genéticaRESUMO
Cells communicate with their environment via surface proteins and secreted factors. Unconventional protein secretion (UPS) is an evolutionarily conserved process, via which distinct cargo proteins are secreted upon stress. Most UPS types depend upon the Golgi-associated GRASP55 protein. However, its regulation and biological role remain poorly understood. Here, we show that the mechanistic target of rapamycin complex 1 (mTORC1) directly phosphorylates GRASP55 to maintain its Golgi localization, thus revealing a physiological role for mTORC1 at this organelle. Stimuli that inhibit mTORC1 cause GRASP55 dephosphorylation and relocalization to UPS compartments. Through multiple, unbiased, proteomic analyses, we identify numerous cargoes that follow this unconventional secretory route to reshape the cellular secretome and surfactome. Using MMP2 secretion as a proxy for UPS, we provide important insights on its regulation and physiological role. Collectively, our findings reveal the mTORC1-GRASP55 signaling hub as the integration point in stress signaling upstream of UPS and as a key coordinator of the cellular adaptation to stress.
Assuntos
Proteínas da Matriz do Complexo de Golgi/genética , Proteoma/genética , Proteômica , Estresse Fisiológico/genética , Matriz Extracelular/genética , Complexo de Golgi/genética , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas de Membrana/genética , Transporte Proteico/genética , Transdução de Sinais/genéticaRESUMO
Heat shock instantly reprograms transcription. Whether gene and enhancer transcription fully recover from stress and whether stress establishes a memory by provoking transcription regulation that persists through mitosis remained unknown. Here, we measured nascent transcription and chromatin accessibility in unconditioned cells and in the daughters of stress-exposed cells. Tracking transcription genome-wide at nucleotide-resolution revealed that cells precisely restored RNA polymerase II (Pol II) distribution at gene bodies and enhancers upon recovery from stress. However, a single heat exposure in embryonic fibroblasts primed a faster gene induction in their daughter cells by increasing promoter-proximal Pol II pausing and by accelerating the pause release. In K562 erythroleukemia cells, repeated stress refined basal and heat-induced transcription over mitotic division and decelerated termination-coupled pre-mRNA processing. The slower termination retained transcripts on the chromatin and reduced recycling of Pol II. These results demonstrate that heat-induced transcriptional memory acts through promoter-proximal pause release and pre-mRNA processing at transcription termination.
Assuntos
Mitose/genética , Regiões Promotoras Genéticas/genética , Estresse Fisiológico/genética , Transcrição Gênica/genética , Linhagem Celular Tumoral , Cromatina/genética , Fibroblastos/fisiologia , Regulação da Expressão Gênica/genética , Genoma/genética , Resposta ao Choque Térmico/genética , Humanos , Células K562 , RNA Polimerase II/genética , RNA Mensageiro/genéticaRESUMO
Stalling during translation triggers ribosome quality control (RQC) to maintain proteostasis. Recently, stalling has also been linked to the activation of integrated stress response (ISR) by Gcn2. How the two processes are coordinated is unclear. Here, we show that activation of RQC by Hel2 suppresses that of Gcn2. We further show that Hel2 and Gcn2 are activated by a similar set of agents that cause ribosome stalling, with maximal activation of Hel2 observed at a lower frequency of stalling. Interestingly, inactivation of one pathway was found to result in the overactivation of the other, suggesting that both are activated by the same signal of ribosome collisions. Notably, the processes do not appear to be in direct competition with each other; ISR prefers a vacant A site, whereas RQC displays no preference. Collectively, our findings provide important details about how multiple pathways that recognize stalled ribosomes coordinate to mount the appropriate response.
Assuntos
Biossíntese de Proteínas , Proteínas Serina-Treonina Quinases/metabolismo , Ribossomos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Estresse Fisiológico , Ubiquitina-Proteína Ligases/metabolismo , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Ribossomos/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Estresse Fisiológico/genética , Fatores de Tempo , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
Developing strategies to activate tumor-cell-intrinsic immune response is critical for improving tumor immunotherapy by exploiting tumor vulnerability. KDM4A, as a histone H3 lysine 9 trimethylation (H3K9me3) demethylase, has been found to play a critical role in squamous cell carcinoma (SCC) growth and metastasis. Here we report that KDM4A inhibition promoted heterochromatin compaction and induced DNA replication stress, which elicited antitumor immunity in SCC. Mechanistically, KDM4A inhibition promoted the formation of liquid-like HP1γ puncta on heterochromatin and stall DNA replication, which activated tumor-cell-intrinsic cGAS-STING signaling through replication-stress-induced cytosolic DNA accumulation. Moreover, KDM4A inhibition collaborated with PD1 blockade to inhibit SCC growth and metastasis by recruiting and activating CD8+ T cells. In vivo lineage tracing demonstrated that KDM4A inhibition plus PD1 blockade efficiently eliminated cancer stem cells. Altogether, our results demonstrate that targeting KDM4A can activate anti-tumor immunity and enable PD1 blockade immunotherapy by aggravating replication stress in SCC cells.
Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Replicação do DNA/genética , Epigênese Genética , Histona Desmetilases/metabolismo , Imunidade/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Estresse Fisiológico/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Homólogo 5 da Proteína Cromobox , Proteínas Cromossômicas não Histona/metabolismo , Dano ao DNA/genética , Células Epiteliais/metabolismo , Deleção de Genes , Humanos , Metástase Linfática , Camundongos Transgênicos , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR3/metabolismo , Células Th1/imunologiaRESUMO
Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why â¼50% of Ewing sarcomas, driven by the EWS-FLI1 fusion oncogene, harbor chromosome 8 gains. Expression of the EWS-FLI1 fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates EWS-FLI1-induced replication stress through gain of a copy of RAD21. Low-level ectopic expression of RAD21 is sufficient to dampen replication stress and improve proliferation in EWS-FLI1-expressing cells. Conversely, deleting one copy in trisomy 8 cells largely neutralizes the fitness benefit of chromosome 8 gain and reduces tumorgenicity of a Ewing sarcoma cancer cell line in soft agar assays. We propose that RAD21 promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.
Assuntos
Carcinogênese/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Sarcoma de Ewing/genética , Estresse Fisiológico/genética , Trissomia/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Cromossomos Humanos Par 8/genética , Replicação do DNA/genética , Proteínas de Ligação a DNA/genética , Duplicação Gênica/genética , Regulação Neoplásica da Expressão Gênica , HumanosRESUMO
Plants cannot move, so they must endure abiotic stresses such as drought, salinity and extreme temperatures. These stressors greatly limit the distribution of plants, alter their growth and development, and reduce crop productivity. Recent progress in our understanding of the molecular mechanisms underlying the responses of plants to abiotic stresses emphasizes their multilevel nature; multiple processes are involved, including sensing, signalling, transcription, transcript processing, translation and post-translational protein modifications. This improved knowledge can be used to boost crop productivity and agricultural sustainability through genetic, chemical and microbial approaches.