Nonsense-mediated mRNA decay and beyond

无义介导的 mRNA 衰减及其他

• 批准号: 10622727
• 负责人: Lynne E Maquat
• 金额: $ 64.13万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622727
• 关键词: Affect; Bacterial Infections; Binding; Biological Process; Biology; COVID-19; Cardiomyopathies; Categories; Cell Nucleus; Cell physiology; Cells; Complex; Cytoplasm; Development; Disease; Environment; Etiology; Exons; Fragile X Syndrome; Frameshift Mutation; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Health; Hereditary Disease; Human; Immune response; In Vitro; Inherited; Innate Immune Response; Intellectual functioning disability; Mammalian Cell; Mediating; Messenger RNA; Metabolism; Mitochondria; Molecular; Mus; Muscle Fibers; Neuromuscular Diseases; Nonsense Codon; Nonsense Mutation; Nuclear; Outcome; Pathogenesis; Pharmacotherapy; Production; Proteins; RNA Cap-Binding Proteins; RNA Polymerase III; RNA Splicing; RNA metabolism; RNA-Binding Proteins; Research; Research Personnel; Role; Runaway; Time; Transcription Coactivator Gene; Translations; Virus Diseases; Work; autism spectrum disorder; boys; cytokine release syndrome; fascinate; girls; human disease; insight; interest; mRNA Decay; mRNA Precursor; mRNA Translation; prevent; protein function; sarcopenia; therapeutically effective

This MIRA application extends our decades-long research on nonsense-mediated mRNA decay (NMD) and how NMD factors can function in other aspects of cellular metabolism. NMD is a fundamental biological process by which mammalian cells eliminate mRNAs containing a nonsense codon deriving from a genetic or acquired frameshift or nonsense mutation. NMD also eliminates an estimated one-third of mRNAs that cells produce by routine mistakes made during gene transcription and/or mRNA production. Over the years, we have worked to elucidate the molecular mechanism of NMD. As one of many outcomes, we have established a “rule” that clinicians and researchers use to predict which nonsense codons result in recessively inherited vs. dominantly inherited disease. We have also demonstrated how cells regulate the efficiency of NMD as an adaptive mechanism during changing environments, e.g. during development, differentiation, or drug treatments. This application pursues our serendipitous finding that NMD is hyperactivated in fragile X syndrome (FXS), which is the most common single-gene cause of intellectual disability and autism, affecting 1/4000 boys and 1/6000-8000 girls. We aim to understand how the protein that is missing in FXS functions via interactions with other proteins and mRNAs to protect these mRNAs from translation and decay. We also aim to decipher the mechanism by which the RNA-binding protein Staufen prevents a runaway immune response. On another front, our long-time interest in mechanistic connections that span pre-mRNA splicing in the nucleus to mRNA translation and decay in the cytoplasm will be extended to include gene transcription and nuclear mRNA decay. We have long been fascinated by the structural dynamics and functions of the largely nuclear cap-binding heterodimer CBP80−CBP20, which binds co-transcriptionally to the 5'-cap of nascent pre-mRNAs. While our past interests have focused on the role of CBP80−CBP20 in the pioneer round(s) of cytoplasmic translation, during which we have shown exon-junction complex-mediated NMD occurs, we aim to understand roles of CBP80−CBP20 in the nucleus. As one example, we are studying the mechanism by which a master transcriptional co-activator of genes whose products regulate critical cellular processes engages with CBP80−CBP20 so as to promote the expression of an understudied category of RNA polymerase III- transcribed genes. In related work, we are studying connections between CBP80−CBP20 and the little- understood, and so-called, nuclear cap-binding protein (NCBP)3. We aim to elucidate the significance of our finding that NCBP3 regulates newly made mRNAs from genes encoding proteins that function in mitochondrial biology. These connections will be examined in skeletal-muscle cells in vitro and ex vivo, the latter using mice, which should lend insight into the etiology and pathogenesis of many human diseases that include sarcopenia, neuromuscular disorders, and cardiomyopathies. While our interests are broad, they are connected by the goal to understand molecular mechanisms in health and in disease, with a focus on RNA metabolism.

这个MIRA应用扩展了我们几十年来对无义介导的mRNA衰变（NMD）和