RUI: Mechanisms of regulation of mitochondrial DNA transcription

RUI：线粒体 DNA 转录调控机制

• 批准号: 1814845
• 负责人: Kristin Dittenhafer-Reed
• 金额: $ 20.79万
• 依托单位: Hope College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1814845&HistoricalAwards=false
• 关键词: RUI; Mechanisms; regulation; mitochondrial; DNA

The goal of this research is to determine how the expression of mitochondrial DNA is regulated to meet the varying energetic demands of a cell. Mitochondria are the metabolic centers of cells and have a small genome that contains instructions to make machinery essential for energy production. This project is expected to provide important advances related to fundamental genetic mechanisms of mammalian cell function. Additionally, the research will provide undergraduate research opportunities to students at Hope College, in order to improve student retention in science and technology. Undergraduate students, with a particular emphasis for selection on women and first year students, will be engaged in all aspects of the project, gaining experience in interdisciplinary research and science communication. Students will be prepared to populate the scientific workforce and become the next generation of scientists capable of addressing complex societal issues.Mitochondrial DNA encodes 13 essential subunits of electron transport chain complexes. The remaining 1500 member mitochondrial proteome, including additional components necessary for energy production and the enzymatic machinery required for mitochondrial DNA expression, is encoded by the nuclear genome. To respond to metabolic changes, mitochondrial gene expression must be coordinated with nuclear gene expression. While the control of nuclear DNA transcription is widely studied, there is a need to understand the mechanisms that control the transcription of mitochondrial DNA. The objective of the project is to determine whether reversible protein post-translational modification regulates mitochondrial DNA transcription. Post-translational modifications, specifically lysine acetylation and serine/threonine phosphorylation, are widely found in the mitochondrial proteome, including on the proteins required for mitochondrial DNA transcription. The research will investigate how these chemical tags provide a means to regulate transcription in response to changes in cellular metabolism. To address this question, a combination of cell biology and protein biochemistry will be used to map the regulatory post-translational modification sites on protein components required for mitochondrial DNA transcription. The biochemical mechanisms by which these sites control transcription will be determined using transcriptional profiling and DNA binding assays. The research is expected to contribute a mechanism explaining the role of post-translational modifications in regulating mitochondrial DNA transcription in response to changing cellular energetic demands. This fundamental knowledge will help advance the understanding of the dynamics and coordination of nuclear and mitochondrial gene transcription.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项研究的目的是确定线粒体DNA的表达是如何调节的，以满足细胞不同的能量需求。线粒体是细胞的代谢中心，它有一个小的基因组，包含制造能量生产所必需的机器的指令。该项目有望为哺乳动物细胞功能的基本遗传机制提供重要进展。此外，该研究将为霍普学院的学生提供本科研究机会，以提高学生在科学和技术方面的保留率。本科生将参与项目的各个方面，获得跨学科研究和科学传播方面的经验，重点是女生和一年级学生。学生将做好准备，成为科学工作者，成为能够解决复杂社会问题的下一代科学家。线粒体DNA编码13个电子传递链复合物的基本亚基。剩下的1500个线粒体蛋白质组成员，包括能量生产和线粒体DNA表达所需的酶机制所需的额外成分，由核基因组编码。为了应对代谢变化，线粒体基因表达必须与核基因表达协调。虽然核DNA转录的控制被广泛研究，但有必要了解控制线粒体DNA转录的机制。该项目的目的是确定可逆的蛋白质翻译后修饰是否调节线粒体DNA转录。翻译后修饰，特别是赖氨酸乙酰化和丝氨酸/苏氨酸磷酸化，广泛存在于线粒体蛋白质组中，包括线粒体DNA转录所需的蛋白质。这项研究将探讨这些化学标签如何提供一种手段来调节转录，以响应细胞代谢的变化。为了解决这个问题，将结合细胞生物学和蛋白质生物化学来绘制线粒体DNA转录所需的蛋白质成分的翻译后修饰位点。这些位点控制转录的生化机制将通过转录谱分析和DNA结合测定来确定。该研究有望为解释翻译后修饰在调节线粒体DNA转录以响应细胞能量需求变化中的作用提供机制。这一基本知识将有助于推进核和线粒体基因转录的动力学和协调的理解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。