Control of Histone mRNA Levels

描述（由申请人提供）：当哺乳动物细胞经历细胞周期时，它们在s期复制染色体。成功的复制不仅需要DNA的复制，还需要合成大量的组蛋白来将新复制的DNA包装到染色质中。组蛋白mrna是一类独特的mrna，是唯一缺乏聚a尾的mrna。它们在保守的茎环中结束，茎环是负责组蛋白mrna在转录后水平协调调节的主要顺式元件。组蛋白mRNA的生物合成需要一个单一的加工反应，切割前mRNA形成成熟的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体来确定直接参与组蛋白前mrna切割的因子，并确定哪些因子参与调节这一过程。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。外行人描述：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，而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。

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.