Control of Histone mRNA Levels

组蛋白 mRNA 水平的控制

• 批准号: 7986704
• 负责人: WILLIAM F. MARZLUFF
• 金额: $ 10.11万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-17 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986704
• 关键词: Anabolism; Binding; Binding Proteins; Cell Cycle; Cell Nucleus; Cells; Chromatin; Chromosomes; Cleaved cell; Complex; Coupled; Cytoplasm; DNA; DNA biosynthesis; Elements; Equilibrium; Genes; Genetic Translation; Grant; Histones; In Vitro; Introns; Mammalian Cell; Mediating; Messenger RNA; Metabolism; Modification; Pathway interactions; Phase; Phosphotransferases; Play; Poly A; Process; Protein Biosynthesis; Proteins; Reaction; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction Pathway; Staging; Structure; System; Tail; Translations; U7 Small Nuclear Ribonucleoprotein; cell growth; chemotherapy; chromosome replication; in vivo; mRNA Precursor; mRNA Transcript Degradation; novel; protein complex

DESCRIPTION (provided by applicant): As mammalian cells go through the cell cycle they replicate their chromosomes during S-phase. Successful replication requires not only replication of DNA but also the synthesis of large amounts of histone proteins to package the newly replicated DNA into chromatin. The histone mRNAs are a unique class of mRNAs and are the only mRNAs that lack a polyA tail. They end instead in a conserved stemloop which is the major cis- element responsible for coordinate regulation of histone mRNAs are the posttranscriptional level. Biosynthesis of histone mRNAs requires a single processing reaction, cleavage of the pre-mRNA to form the mature mRNA. This reaction is regulated during the cell cycle, as is the stability of histone mRNA. We propose to identify the factor(s) directly involved in cleavage of histone pre-mRNA, by purifying the processing complex and to also identify which of these factors that are involved in regulating this process. Histone mRNAs are rapidly degraded when DNA replication is inhibited. We will determine the pathway of histone mRNA degradation and the factors involved in initiating and regulating the degradation of histone mRNAs. Finally we will elucidate the signal transduction pathways that transmit the information that DNA replication has ceased in the nucleus to degradation of the histone mRNA in the cytoplasm. Laymans description: Histone proteins are the proteins complexed with DNA in the chromosomes. Proper chromosome replication requires synthesis of both DNA and histones, and these two processes are tightly coupled. We will determine the factors critical for both histone mRNA synthesis and degradation, and novel factors provide potential new chemotherapy targets, as well as helping us to understand the control of cell growth.

描述（由申请人提供）：当哺乳动物细胞经历细胞周期时，它们会在 S 期复制染色体。成功的复制不仅需要复制DNA，还需要合成大量的组蛋白，将新复制的DNA包装到染色质中。组蛋白 mRNA 是一类独特的 mRNA，并且是唯一缺少多聚腺苷酸尾巴的 mRNA。相反，它们以保守的茎环结尾，这是负责转录后水平的组蛋白 mRNA 协调调节的主要顺式元件。组蛋白 mRNA 的生物合成需要单个加工反应，即前体 mRNA 的裂解以形成成熟的 mRNA。该反应在细胞周期中受到调节，组蛋白 mRNA 的稳定性也是如此。我们建议通过纯化加工复合物来鉴定直接参与组蛋白前体 mRNA 切割的因子，并鉴定其中哪些因子参与调节该过程。当 DNA 复制受到抑制时，组蛋白 mRNA 会迅速降解。我们将确定组蛋白 mRNA 降解的途径以及参与启动和调节组蛋白 mRNA 降解的因素。最后我们将阐明将细胞核中 DNA 复制已停止的信息传递到细胞质中组蛋白 mRNA 降解的信号转导途径。外行描述：组蛋白是染色体中与DNA复合的蛋白质。正确的染色体复制需要 DNA 和组蛋白的合成，并且这两个过程紧密耦合。我们将确定对组蛋白 mRNA 合成和降解至关重要的因素，新的因素提供潜在的新化疗靶点，并帮助我们了解细胞生长的控制。