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: 7666076
• 负责人: Wen-Hwa Lee
• 金额: $ 30.76万
• 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/7666076
• 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）：线粒体在生命中起着至关重要的作用，其完整性是生物体中的关键问题。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受到突变，因为它在该细胞器中产生的高活性氧（ROS）以及低水平的DNA修复。因此，发现与ROS相关的突变发现结肠癌中约70％的线粒体基因组。 SUV3是线粒体RNA降解体的组成部分。在酵母中，SUV3的灭活会导致线粒体功能障碍和线粒体DNA的丧失，这表明SUV3对于保护线粒体基因组稳定性至关重要。但是，尚不知道SUV3在哺乳动物中的作用。在我们的初步研究中，我们表明两个SUV3等位基因的失活都导致早期的小鼠胚胎致死性，并且杂合小鼠表现出早期衰老的衰老早期表现型，其特征是寿命缩短和倾向，使肿瘤的肿瘤具有90％的渗透率，表明SUV3是SUV3是一种新颖的tumor抑制剂。这些患病的表型可以用野生型雌性而不是雄性小鼠从十字架衍生而来的后代救出，这表明SUV3的主要作用是通过线粒体介导的。一致地，SUV3在人类细胞中的耗竭会导致截短的线粒体RNA的积累以及ROS产生和凋亡的增加。线粒体RNA降解是一个严格监测的过程。在大肠杆菌中，包括RNase E，RHLB，PNPase和Enolase在内的四个主要成分构成降解体。在哺乳动物中，在线粒体中发现了SUV3和PNPase。最近，我们发现SUV3在进化上既融合了原始降解体的解旋酶和内核酸酶活性活动，因为SUV3（如RHLB）具有解旋酶和ATPase活性，并包含rnase E. rnase E.但是，rnase E.但是如何与pnpase and pnpase and pnpase Ansightrair andna pernurial pernurial nna perna perna rnase Etna rnase contra rna perna perna rnna perna perna rnna perna perna rnecoration rnecoration。导致导致癌症或衰老表型的线粒体功能障碍是令人着迷的问题。在此应用中，我们关注以下三个特定目标：目标1是系统地研究SUV3杂合子的线粒体功能的过早衰老表型和异常。目的2是描述SUV3保守域在RNA降解中的生物学和生化作用。目标3是识别和表征构成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。这些研究得出的结果将提供分子基础，以解释SUV3如何在衰老过程和肿瘤发生中起作用。公共卫生相关性：线粒体功能障碍会导致许多疾病，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降解中起着至关重要的作用，以及该过程的扰动如何导致线粒体功能障碍导致癌症和衰老表型的线粒体功能障碍尚不清楚。我们计划使用SUV3杂合小鼠研究线粒体RNA降解的异常。这些研究得出的结果将提供分子基础，以解释SUV3介导的RNA降解如何在衰老过程和肿瘤发生中起作用。