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首页> 外文学位 >Examining the role of the U7 snRNA in histone pre-mRNA processing and the U7 snRNP dependent and independent roles of Lsm10 and Lsm11, two novel Lsm proteins in Drosophila.
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Examining the role of the U7 snRNA in histone pre-mRNA processing and the U7 snRNP dependent and independent roles of Lsm10 and Lsm11, two novel Lsm proteins in Drosophila.

机译：检查U7 snRNA在组蛋白前mRNA加工中的作用以及果蝇中的两个新型Lsm蛋白Lsm10和Lsm11的U7 snRNP依赖性和独立作用。

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摘要

Cell cycle regulated histone gene expression ensures that the correct amounts of histones are synthesized each S phase, and is controlled in large part by the unique 3' end of histone mRNA, which terminates in a conserved stem-loop structure generated by an endonucleolytic cleavage, rather than a polyA tail. Histone 3' end formation involves a pre-mRNA processing reaction requiring a protein that binds the stem loop (SLBP), and the U7 snRNP, which interacts with a purine rich sequence, called the HDE (Histone Downstream Element), downstream of the cleavage site in histone pre-mRNA. The U7 snRNP is related to the spliceosomal snRNPs, small noncoding RNAs bound by a seven member Sm protein ring, but its protein ring contains two unique proteins, Lsm10 and Lsm11, and its only known function is in histone pre-mRNA processing. Much of this molecular model has been obtained from in vitro studies. In this thesis we characterize the U7 snRNP and its two unique proteins, Lsm10 and Lsm11, genetically and molecularly in order to determine their role in cell cycle regulated histone expression in vivo, and during development in Drosophila melanagaster.;We have created null alleles of the U7 snRNA and found that they result in the production of polyadenylated histone mRNA from the use of cryptic polyadenlyation signals downstream of the normal processing site. A similar molecular phenotype also results from mutation of Slbp, but U7 null mutants survive to adulthood and are male and female sterile while Slbp null mutants are lethal. This difference in terminal phenotype may reflect a later onset of the histone pre-mRNA processing defect in U7 null mutants compared to Slbp null mutants. In Slbp null mutants, misprocessed histone mRNA is seen as early as the embryo stage of development while in U7 null mutants the misprocessed histone mRNA does not appear until the second instar stage of development, due to the maternal stores of U7 snRNA.;We have also analyzed mutations of the Lsm10 and Lsm11 genes and found that those mutations result in the same misprocessed histone mRNA phenotype as U7 null mutants, but both mutations are lethal. We have shown that the difference in terminal phenotype is not due to an earlier onset of misprocessed histone mRNA, but instead could be due to a role(s) for Lsm10 and Lsm11 outside of histone pre-mRNA processing that is U7 independent. We have also shown that there is U7 snRNA still present in an Lsm11 null mutant. The RNA can be pulled down using TMG coupled beads suggesting that the U7 snRNA is bound by snRNP proteins even though Lsm10 and Lsm11 are not present. However this snRNA does not localize to the Histone Locus Body (HLB) suggesting that both Lsm10 and Lsm11 are required for U7 snRNP localization to the HLB.
机译：细胞周期调节的组蛋白基因表达可确保在每个S期合成正确量的组蛋白，并在很大程度上受组蛋白mRNA独特的3'端控制，该3'端终止于核酸内切裂解产生的保守茎环结构，而不是polyA的尾巴。组蛋白3'末端形成涉及mRNA加工前反应，该蛋白需要与茎环（SLBP）结合的蛋白，以及U7 snRNP，其与裂解下游的富含嘌呤的序列（称为HDE（组蛋白下游元件））相互作用组蛋白前mRNA中的位点。 U7 snRNP与剪接体snRNPs有关，后者是由七个成员Sm蛋白环结合的小的非编码RNA，但其蛋白环包含两个独特的蛋白Lsm10和Lsm11，其唯一已知的功能是在组蛋白前mRNA加工中。这种分子模型大部分是通过体外研究获得的。在本文中，我们通过基因和分子生物学方法表征了U7 snRNP及其两个独特的蛋白Lsm10和Lsm11，以确定它们在果蝇体内和体内发育过程中在细胞周期调控组蛋白表达中的作用。 U7 snRNA，发现它们可通过使用正常加工位点下游的隐伏聚腺苷酸化信号来产生聚腺苷酸组蛋白mRNA。 Slbp突变也产生相似的分子表型，但是U7无效突变体可以存活到成年，并且是雄性和雌性不育的，而Slbp无效突变体则是致命的。与Slbp无效突变体相比，末端表型的这种差异可能反映了U7无效突变体中组蛋白前mRNA加工缺陷的后期发作。在Slbp无效突变体中，误加工的组蛋白mRNA最早见于发育的胚胎阶段，而在U7无效突变体中，由于发育中的U7 snRNA的母体储存，直到第二龄发育阶段才出现加工不当的组蛋白mRNA。他们还分析了Lsm10和Lsm11基因的突变，发现这些突变导致与U7无效突变体相同的组蛋白mRNA表型处理错误，但是这两个突变都是致命的。我们已经表明，终端表型的差异不是由于组蛋白mRNA加工较早而引起的，而是由于Lsm10和Lsm11在组蛋白前mRNA加工之外的作用是独立于U7的。我们还显示，Lsm11空突变体中仍存在U7 snRNA。可以使用TMG偶联珠将RNA下拉，这表明即使不存在Lsm10和Lsm11，U7 snRNA仍被snRNP蛋白结合。但是，此snRNA不会定位到组蛋白基因座体（HLB），这表明L7和U11都需要Lsm10和Lsm11才能定位到HLB。

著录项

  • 作者

    Godfrey, Ashley C.;

  • 作者单位

    The University of North Carolina at Chapel Hill.;

  • 授予单位 The University of North Carolina at Chapel Hill.;
  • 学科 Biology Molecular.;Biology Genetics.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 150 p.
  • 总页数 150
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;遗传学;细胞生物学;
  • 关键词

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