RESUMEN
Across the animal kingdom, adult tissue homeostasis is regulated by adult stem cell activity, which is commonly dysregulated in human cancers. However, identifying key regulators of stem cells in the milieu of thousands of genes dysregulated in a given cancer is challenging. Here, using a comparative genomics approach between planarian adult stem cells and patient-derived glioblastoma stem cells (GSCs), we identify and demonstrate the role of DEAD-box helicase DDX56 in regulating aspects of stemness in four stem cell systems: planarians, mouse neural stem cells, human GSCs, and a fly model of glioblastoma. In a human GSC line, DDX56 localizes to the nucleolus, and using planarians, when DDX56 is lost, stem cells dysregulate expression of ribosomal RNAs and lose nucleolar integrity prior to stem cell death. Together, a comparative genomic approach can be used to uncover conserved stemness regulators that are functional in both normal and cancer stem cells.
Asunto(s)
ARN Helicasas DEAD-box/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Adultas/metabolismo , Animales , Línea Celular Tumoral , Linaje de la Célula , Nucléolo Celular/metabolismo , Proliferación Celular , Autorrenovación de las Células , Supervivencia Celular , Corteza Cerebral/citología , ARN Helicasas DEAD-box/genética , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Regulación Neoplásica de la Expresión Génica , Genómica , Glioblastoma/genética , Glioblastoma/patología , Células HEK293 , Humanos , Ratones , Modelos Biológicos , Células Madre Neoplásicas/patología , Células-Madre Neurales/metabolismo , Planarias/citología , Planarias/metabolismo , Interferencia de ARN , Subunidades Ribosómicas/metabolismo , Resultado del Tratamiento , Regulación hacia Arriba/genéticaRESUMEN
Whole-genome duplication has played a central role in the genome evolution of many organisms, including the human genome. Most duplicated genes are eliminated, and factors that influence the retention of persisting duplicates remain poorly understood. We describe a systematic complex genetic interaction analysis with yeast paralogs derived from the whole-genome duplication event. Mapping of digenic interactions for a deletion mutant of each paralog, and of trigenic interactions for the double mutant, provides insight into their roles and a quantitative measure of their functional redundancy. Trigenic interaction analysis distinguishes two classes of paralogs: a more functionally divergent subset and another that retained more functional overlap. Gene feature analysis and modeling suggest that evolutionary trajectories of duplicated genes are dictated by combined functional and structural entanglement factors.
Asunto(s)
Duplicación de Gen , Genes Duplicados , Genoma Fúngico , Mapas de Interacción de Proteínas/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Eliminación de Gen , Redes Reguladoras de Genes , Técnicas Genéticas , Proteínas de la Membrana/genética , Peroxinas/genéticaRESUMEN
To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic interaction network and tested for a genetic interaction with a third mutation. Trigenic interactions often occurred among functionally related genes, and essential genes were hubs on the trigenic network. Despite their functional enrichment, trigenic interactions tended to link genes in distant bioprocesses and displayed a weaker magnitude than digenic interactions. We estimate that the global trigenic interaction network is ~100 times as large as the global digenic network, highlighting the potential for complex genetic interactions to affect the biology of inheritance, including the genotype-to-phenotype relationship.
Asunto(s)
Redes Reguladoras de Genes , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Mutación , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
The repositioning or "repurposing" of existing therapies for alternative disease indications is an attractive approach that can save significant investments of time and money during drug development. For cancer indications, the primary goal of repurposed therapies is on efficacy, with less restriction on safety due to the immediate need to treat this patient population. This report provides a high-level overview of how drug developers pursuing repurposed assets have previously navigated funding efforts, regulatory affairs, and intellectual property laws to commercialize these "new" medicines in oncology. This article provides insight into funding programs (e.g., government grants and philanthropic organizations) that academic and corporate initiatives can leverage to repurpose drugs for cancer. In addition, we highlight previous examples where secondary uses of existing, Food and Drug Administration- or European Medicines Agency-approved therapies have been predicted in silico and successfully validated in vitro and/or in vivo (i.e., animal models and human clinical trials) for certain oncology indications. Finally, we describe the strategies that the pharmaceutical industry has previously employed to navigate regulatory considerations and successfully commercialize their drug products. These factors must be carefully considered when repurposing existing drugs for cancer to best benefit patients and drug developers alike.