Regulation of pre-ribosomal RNA by the Circadian Clock

项目摘要 通过时差、睡眠不足或倒班工作等方式扰乱人体内部生物钟可能 影响生物功能并导致疾病。更加熟悉昼夜节律的调节 将有助于更好地了解肥胖、糖尿病和癌症等病理及其发展 这些疾病的治疗方法。 在分子尺度上，生物钟控制着许多细胞机制，这些机制赋予生物钟 能够保持24小时不变的状态。核心时钟机械Clock和BMAL1调节 时钟控制基因的转录。此外，时钟还被发现具有非传统的作用 在翻译后修饰中，例如昼夜节律蛋白质的乙酰化水平。然而，其他角色 BMAL1的基因没有得到很好的鉴定。最近的发现提供的线索表明，时钟与RNA有关 聚合酶1(Pol I)介导的转录。POL I转录核糖体DNA(RDNA)，进一步加工 通过一系列转录后修饰来成熟核糖体RNA(RRNA)。RRNA前体， (Pre-rRNA)，是一个包含18S、5.8S和28S rRNA的串联重复序列。昼夜节律核蛋白的研究 积累显示了参与前rRNA的核仁蛋白的振荡表达模式 正在处理。根据最近的发现，这个项目的目标是阐明昼夜节律的功能 调节Pre-rRNA的时钟。 这项研究将探索尚未发现的昼夜节律前rRNA表达的机制。第一，一部小说 BMal1的亚细胞定位将被识别和充分表征。此外，Pre-Pre的昼夜节律 将通过预分析来研究rRNA，以定位BMAL1与rDNA的募集位点。 以时钟依赖的方式测量Pol I转录活性将定义Pol I转录活性的作用 关于前rRNA转录的生物钟。 此外，这项研究将确定BMAL1在前rRNA成熟中的一个新角色。它的重要性 BMAL1和核仁蛋白之间的物理相互作用将得到彻底确立。紧接着是 对生物钟在核仁结构完整性上的作用的综合分析。最后，我们将测试 核仁BMAL1在前rRNA加工中的意义。我们相信我们将描述功能性的 核仁中BMAL1的相关性。 好了！

Project Summary Disruptions of the body's internal circadian clock by means such as jet lag, a lack of sleep or shift work can affect biological functions and lead to disease. Becoming more familiar with the regulation of circadian rhythms will allow for a better understanding of pathologies such as obesity, diabetes, and cancer and the development of therapeutic treatments for these diseases. On a molecular scale, the circadian clock controls many cellular mechanisms that give the biological clock the ability to remain at a constant 24-hour period. The core clock machinery, CLOCK and BMAL1, regulates transcription of clock-controlled genes. Additionally, CLOCK has also been found to have a non-traditional role in post-translational modifications such as the acetylation levels of circadian proteins. However, additional roles for BMAL1 are not well identified. Hints provided by recent discoveries indicate the clock is involved RNA polymerase 1 (Pol I)-mediated transcription. Pol I transcribes ribosomal DNA (rDNA) that is further processed to mature ribosomal RNA (rRNA) through a series of post-transcriptional modifications. The rRNA precursor, (pre-rRNA), is a tandem repeat that contains 18S, 5.8S and 28S rRNAs. A study on circadian nuclear protein accumulation has shown an oscillatory expression pattern of nucleolar proteins involved in pre-rRNA processing. Based on the recent findings, the goal of this project is to elucidate the function of the circadian clock on the regulation of pre-rRNA. This study will explore the undiscovered mechanism for the circadian pre-rRNA expression. First, a novel BMAL1 subcellular localization will be identified and fully characterized. Further, the circadian regulation of pre- rRNA will be investigated by preforming analyses to locate the sites of BMAL1 recruitment to rDNA. Measurements of the Pol I transcriptional activity in a clock-dependent manner will define the role of the circadian clock on pre-rRNA transcription. Additionally, this research study will identify a novel role for BMAL1 on pre-rRNA maturation. The importance of a physical interaction between BMAL1 and the nucleolar proteins will be thoroughly established. Followed by a comprehensive analysis of the role of the circadian clock on nucleolar structural integrity. Lastly, we will test the significance of the nucleolar BMAL1 in pre-rRNA processing. We believe we will characterize the functional relevance of BMAL1 in the nucleolus. !