Mitochondrial Roles of the SUV3 in Premature Aging and Cancer

SUV3 的线粒体在过早衰老和癌症中的作用

• 批准号: 7881437
• 负责人: Wen-Hwa Lee
• 金额: $ 30.37万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881437
• 关键词: ATP phosphohydrolase; Address; Age; Aging; Aging-Related Process; Alleles; Apoptosis; Biochemical; Biological; Cell physiology; Cells; Collaborations; Colon Carcinoma; Coupled; DNA Repair; Disease; Embryo; Endoribonucleases; Escherichia coli; Exhibits; Failure; Female; Generations; Genome; Genome Stability; Genomic Instability; Heterozygote; Human; Life; Longevity; Maintenance; Malignant Neoplasms; Mammals; Mediating; Mitochondria; Mitochondrial DNA; Mitochondrial RNA; Molecular; Monitor; Mus; Mutation; Organelles; Organism; Penetrance; Phenotype; Play; Predisposition; Premature aging syndrome; Process; Production; RNA Degradation; RNA Interference; RNA degradosome; Reactive Oxygen Species; Role; Testing; Tumor Suppressor Proteins; Yeasts; base; degradosome; endoribonuclease; enolase; fascinate; helicase; male; mitochondrial dysfunction; mitochondrial genome; mutant; novel; offspring; public health relevance; ribonuclease E; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Mitochondria play an essential role in life and its integrity is a critical issue in organisms. Failure in maintenance of mitochondrial integrity causes numerous diseases including cancer and aging. The mitochondria genome is particularly susceptible to mutations because of its high level of reactive oxygen species (ROS) generated in this organelle, coupled with the low level of DNA repair. Accordingly, about 70% of the mitochondria genome in colon cancers was found with a ROS-related mutation. SUV3 is known to be a component of mitochondrial RNA degradosome. In yeast, inactivation of Suv3 leads to mitochondrial dysfunction and loss of mitochondrial DNA, suggesting that SUV3 is essential for guarding mitochondrial genome stability. However, it is not known what role SUV3 plays in mammals. In our preliminary studies, we showed that inactivation of both SUV3 alleles leads to early mouse embryonic lethality, and that heterozygous mice exhibited an early aging-phenotype, characterized by a shortened life span and predisposition to a broad spectrum of tumors with 90% penetrance, suggesting that SUV3 is a novel tumor suppressor. These diseased phenotypes can be rescued in offspring derived from the cross with wild-type female, but not male mice, suggesting that the major effect of SUV3 is mediated through mitochondria. Consistently, depletion of SUV3 in human cells leads to accumulation of the truncated mitochondrial RNA and an increase of ROS production and apoptosis. Mitochondrial RNA degradation is a tightly monitored process. In E. coli, four major components including RNase E, RhlB, PNPase and enolase constitute the degradosome. In mammals, SUV3 and PNPase were found in mitochondria. Recently, we found that SUV3 has evolutionarily converged both the helicase and the endoribonuclease activities of the primordial degradosome because SUV3, like RhlB, has helicase and ATPase activities and contains an endoribonuclease activity, like RNase E. However, how SUV3 in collaboration with PNPase plays an essential role in mitochondrial RNA degradation and how perturbation of this process contributes to mitochondrial dysfunction leading to cancer or aging phenotype are fascinating questions. In this application, we focus on three specific aims as follows: Aim 1 is to investigate systematically the premature ageing phenotypes and abnormalities of mitochondrial function of SUV3 heterozygotes. Aim 2 is to delineate biological and biochemical roles of the conserved domains of SUV3 in RNA degradation. And Aim 3 is to identify and characterize major components constituting mammalian mitochondrial degradosome as well as to elucidate their contribution in mitochondrial RNA degradation. Results derived from these studies will provide a molecular basis to explain how SUV3 plays a role in aging process and tumorigenesis. PUBLIC HEALTH RELEVANCE: Mitochondrial dysfunction causes numerous diseases including cancer and aging. SUV3 is a component of the mitochondrial RNA degradosome. How SUV3 plays an essential role in mitochondrial RNA degradation and how perturbation of this process contributes to mitochondrial dysfunction leading to cancer and aging phenotype are completely unclear. We plan to use SUV3 heterozygous mice to investigate the abnormalities of mitochondrial RNA degradation. Results derived from these studies will provide a molecular basis to explain how SUV3-mediated RNA degradation plays a role in the aging process and tumorigenesis.

描述（由申请人提供）：线粒体在生命中发挥着重要作用，其完整性是生物体中的一个关键问题。维持线粒体完整性的失败会导致许多疾病，包括癌症和衰老。线粒体基因组特别容易发生突变，因为该细胞器中产生的活性氧 (ROS) 水平很高，而且 DNA 修复水平较低。因此，结肠癌中约 70% 的线粒体基因组被发现存在 ROS 相关突变。 SUV3 已知是线粒体 RNA 降解体的组成部分。在酵母中，Suv3 失活会导致线粒体功能障碍和线粒体 DNA 丢失，这表明 SUV3 对于保护线粒体基因组稳定性至关重要。然而，SUV3 在哺乳动物中扮演什么角色尚不清楚。在我们的初步研究中，我们表明，两个 SUV3 等位基因的失活会导致早期小鼠胚胎致死，并且杂合子小鼠表现出早期衰老表型，其特征是寿命缩短和易患广谱肿瘤，外显率达 90%。表明 SUV3 是一种新型肿瘤抑制因子。这些患病表型可以在与野生型雌性小鼠而非雄性小鼠杂交的后代中得到挽救，这表明 SUV3 的主要作用是通过线粒体介导的。一致地，人类细胞中 SUV3 的消耗会导致截短的线粒体 RNA 的积累以及 ROS 产生和细胞凋亡的增加。线粒体 RNA 降解是一个受到严格监控的过程。在大肠杆菌中，降解体由四种主要成分组成，包括RNase E、RhlB、PNPase和烯醇化酶。在哺乳动物中，SUV3 和 PNPase 存在于线粒体中。最近，我们发现SUV3在进化上趋同了原始降解体的解旋酶和核糖核酸内切酶活性，因为SUV3像RhlB一样，具有解旋酶和ATPase活性，并且包含核糖核酸内切酶活性，如RNase E。然而，SUV3如何与PNPase合作发挥作用在线粒体 RNA 降解中发挥重要作用，以及该过程的扰动如何导致线粒体功能障碍，从而导致癌症或衰老表型是令人着迷的问题。在本申请中，我们重点关注以下三个具体目标：目标1是系统研究SUV3杂合子的早衰表型和线粒体功能异常。目标 2 是描述 SUV3 保守结构域在 RNA 降解中的生物学和生化作用。目标 3 是鉴定和表征哺乳动物线粒体降解体的主要成分，并阐明它们在线粒体 RNA 降解中的贡献。这些研究的结果将为解释 SUV3 如何在衰老过程和肿瘤发生中发挥作用提供分子基础。公共卫生相关性：线粒体功能障碍会导致多种疾病，包括癌症和衰老。 SUV3 是线粒体 RNA 降解体的组成部分。 SUV3 如何在线粒体 RNA 降解中发挥重要作用，以及该过程的扰动如何导致线粒体功能障碍，从而导致癌症和衰老表型，目前尚不清楚。我们计划使用SUV3杂合子小鼠来研究线粒体RNA降解的异常情况。这些研究的结果将为解释 SUV3 介导的 RNA 降解如何在衰老过程和肿瘤发生中发挥作用提供分子基础。