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）：随着哺乳动物细胞经历细胞周期，它们在S期复制其染色体。成功的复制不仅需要DNA的复制，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，并且是唯一缺乏polyA尾的mRNA。相反，它们以保守的茎环结束，茎环是在转录后水平负责协调调节组蛋白mRNA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的切割以形成成熟mRNA。这种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mRNA切割的因子，并鉴定哪些因子参与调节该过程。当DNA复制被抑制时，组蛋白mRNA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，我们将阐明信号转导途径，传递的信息，DNA复制已停止在细胞核中的组蛋白mRNA在细胞质中的降解。通俗描述：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，这两个过程是紧密耦合的。我们将确定组蛋白mRNA合成和降解的关键因素，新的因素提供了潜在的新的化疗靶点，并帮助我们了解细胞生长的控制。