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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

基本信息

批准号：
8284339
负责人：
Wen-Hwa Lee
金额：
$ 28.99万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8284339
关键词：
ATP phosphohydrolase Address 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 Health 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 ribonuclease E tumor tumorigenesis

项目摘要

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，其完整性是生物体的关键问题。线粒体完整性维持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，因为其细胞器中产生的活性氧（ROS）水平高，加上DNA修复水平低。因此，结肠癌中约70%的线粒体基因组被发现具有ros相关突变。已知SUV3是线粒体RNA降解体的一个组成部分。在酵母中，Suv3的失活导致线粒体功能障碍和线粒体DNA的丢失，这表明Suv3对于保护线粒体基因组的稳定性至关重要。然而，目前尚不清楚SUV3在哺乳动物中扮演什么角色。在我们的初步研究中，我们发现两个SUV3等位基因的失活导致小鼠早期胚胎死亡，杂合小鼠表现出早期衰老表型，其特征是寿命缩短，易患广谱肿瘤，外显率为90%，这表明SUV3是一种新的肿瘤抑制因子。这些病变表型可以在与野生型雌性小鼠杂交的后代中恢复，但不能在雄性小鼠中恢复，这表明SUV3的主要作用是通过线粒体介导的。与此一致的是，人类细胞中SUV3的缺失导致截断的线粒体RNA的积累，ROS的产生和细胞凋亡的增加。线粒体RNA降解是一个严密监控的过程。在大肠杆菌中，由RNase E、RhlB、PNPase和烯醇化酶四种主要组分组成降解体。哺乳动物线粒体中发现了SUV3和PNPase。最近，我们发现SUV3在进化上收敛了原始降解体的解旋酶和核糖核酸内酶活性，因为SUV3和RhlB一样具有解旋酶和atp酶活性，并且含有核糖核酸内酶活性，如RNase e。SUV3如何与PNPase合作在线粒体RNA降解中发挥重要作用，以及这一过程的扰动如何导致线粒体功能障碍导致癌症或衰老表型是令人着迷的问题。在这项应用中，我们关注以下三个具体目标：目标1是系统地研究SUV3杂合子的早衰表型和线粒体功能异常。目的2是描述SUV3的保守结构域在RNA降解中的生物学和生化作用。目的3是鉴定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降解中的作用。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：线粒体功能障碍导致许多疾病，包括癌症和衰老。SUV3是线粒体RNA降解体的一个组成部分。SUV3如何在线粒体RNA降解中发挥重要作用，以及这一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完全不清楚。我们计划使用SUV3杂合小鼠来研究线粒体RNA降解的异常。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。