The FRH DEXH box helicase: analysis of a core component of the Neurospora circadi

FRH DEXH 盒式解旋酶：圆脉脉孢菌核心成分的分析

• 批准号: 8059480
• 负责人: Jennifer Hurley
• 金额: $ 4.84万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059480
• 关键词: Affect; Alleles; Animals; Architecture; Awareness; Behavioral; Binding; Biochemical; Boxing; Cardiovascular Diseases; Cells; Circadian Rhythms; Co-Immunoprecipitations; Complex; Cues; Cyanobacterium; Ecology; Effectiveness; Elements; Escherichia coli; Family; Frequencies; Gene Frequency; Genes; Health; Homologous Gene; Hour; Human; Knock-out; Life; Link; Malignant Neoplasms; Mass Spectrum Analysis; Medical; Mental disorders; Messenger RNA; Neurospora; Periodicity; Physiological; Play; Process; Protein Family; Proteins; RNA; RNA Helicase; Role; SKIV2L gene; Sequence Homology; Signal Transduction; Sleep Disorders; System; Time; Work; cell growth; cellular development; circadian pacemaker; helicase; human disease; insight; mutant; novel; protein expression; response; white collar 1

DESCRIPTION (provided by applicant): Circadian rhythms are a roughly 24-hour cycle in the biochemical, physiological or behavioral processes of living entities and are present from animals to cyanobacteria. A circadian rhythm is defined as a cycle that has a period of about a single day, can persist in the absence of time cues while retaining the ability to be reset by them, and is not affected by signals outside these cues. The proteins that constitute the core components of the Neurospora clock, one of the best-studied circadian systems, include Frequency (FRQ), White Collar 1 (WC-1), White Collar 2 (WC-2) and Frequency Interacting RNA Helicase (FRH). While the first three components are well studied, many questions remain about the role that FRH plays in the function of the Neurospora clock. The aim of this work is to identify the function of FRH in the Neurospora circadian clock. To investigate this mechanism, I will use a multi-facetted approach. In Specific Aim 1, I will identify the regions of FRH that are essential to cellular growth and development, and distinguish them from regions that are related to the function of the circadian clock using the FRHR806H strain; a strain in which the rhythmicity of the clock is knocked out while maintaining the health of the strain. In Specific Aim 2, to further understand the function and importance of FRH, I will look at the interactions between the other core components and FRH, while identifying the regions of FRH important for each interaction. In Specific Aim 3, I will determine the RNA targets of FRH and explore its role as an mRNA interacting protein, a function that is suggested by its homology to the DEAD box family of proteins, in particular the DSHCT family. Because of its similarity to DEAD-box proteins it is logical to assert that FRH may facilitate the interaction of clock controlled gene mRNAs with necessary partners. This would demonstrate an entirely new level of control in the circadian system. Given the many and strong similarities between fungal and animal clocks, specifically including the conservation of regulatory architecture and components, understanding the function of a new family of proteins involved at the core of the circadian rhythm broadens the horizons of how we understand the clock mechanism. Identifying the specific role of this new player will tease out yet another level of awareness as to the sensitivity and response of the clock. Since the Neurospora clock is often used to understand the human clock, this could give us greater insight into our cycle and all of the implications that are associated with it, from ecology to human disease. PUBLIC HEALTH RELEVANCE: Given the many and strong similarities between fungal and animal clocks, understanding the function of a new family of proteins involved at the core of the circadian rhythm broadens the horizons of how we understand the clock mechanism (1). The effectiveness of medical treatment, sleep disorders, psychiatric disorders, cardiovascular disease, and cancer have all been linked to the rhythm of the circadian clock (2-6). Since the Neurospora clock is often used to understand the human clock, this could give us greater insight into our cycle and all of the implications that are associated with it.

描述（由申请人提供）：昼夜节律是生物体的生化、生理或行为过程中大约 24 小时的周期，从动物到蓝藻都存在。昼夜节律被定义为一个周期约为一天的周期，可以在没有时间线索的情况下持续存在，同时保留由时间线索重置的能力，并且不受这些线索之外的信号的影响。脉孢菌钟是研究最深入的昼夜节律系统之一，构成脉孢菌钟核心成分的蛋白质包括频率 (FRQ)、白领 1 (WC-1)、白领 2 (WC-2) 和频率相互作用 RNA 解旋酶 ( FRH）。虽然前三个组成部分已得到充分研究，但关于 FRH 在脉孢菌钟功能中所发挥的作用仍然存在许多问题。 这项工作的目的是确定 FRH 在脉孢菌生物钟中的功能。为了研究这个机制，我将使用多方面的方法。在具体目标 1 中，我将使用 FRHR806H 菌株识别 FRH 对细胞生长和发育至关重要的区域，并将其与与生物钟功能相关的区域区分开来；在保持菌株健康的同时，时钟节律性被破坏的菌株。在具体目标 2 中，为了进一步了解 FRH 的功能和重要性，我将研究其他核心组件与 FRH 之间的相互作用，同时确定 FRH 对每个相互作用重要的区域。在具体目标 3 中，我将确定 FRH 的 RNA 靶标并探索其作为 mRNA 相互作用蛋白的作用，该功能由其与 DEAD box 蛋白家族（特别是 DSHCT 家族）的同源性所暗示。由于其与 DEAD-box 蛋白的相似性，可以合理地断言 FRH 可能促进时钟控制基因 mRNA 与必要伙伴的相互作用。这将展示昼夜节律系统的全新控制水平。 鉴于真菌和动物生物钟之间存在许多强烈的相似性，特别是包括调节结构和成分的保护，了解参与昼夜节律核心的新蛋白质家族的功能拓宽了我们理解生物钟机制的视野。确定这位新玩家的具体角色将进一步提高人们对时钟灵敏度和响应的认识。由于脉孢菌时钟经常被用来理解人类时钟，这可以让我们更深入地了解我们的周期以及与之相关的所有影响，从生态到人类疾病。 公共健康相关性：鉴于真菌和动物生物钟之间存在许多强烈的相似性，了解参与昼夜节律核心的新蛋白质家族的功能可以拓宽我们理解生物钟机制的视野 (1)。药物治疗、睡眠障碍、精神疾病、心血管疾病和癌症的有效性都与生物钟的节律有关 (2-6)。由于脉孢菌时钟经常被用来理解人类时钟，这可以让我们更深入地了解我们的周期以及与之相关的所有含义。