Mitochondrial Roles of the SUV3 in Premature Aging and Cancer

描述(申请人提供)：线粒体在生命中扮演着重要的角色，其完整性是生物体中的一个关键问题。未能维持线粒体的完整性会导致许多疾病，包括癌症和衰老。线粒体基因组特别容易受到突变的影响，因为它在这个细胞器中产生了高水平的活性氧物种(ROS)，再加上低水平的DNA修复。因此，在结肠癌中发现了大约70%的线粒体基因组存在与ROS相关的突变。已知SUV3是线粒体RNA降解体的一个组成部分。在酵母中，Suv3的失活会导致线粒体功能障碍和线粒体DNA的丢失，这表明SuV3对于保卫线粒体基因组的稳定性是必不可少的。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等位基因的失活都会导致小鼠早期胚胎死亡，杂合子小鼠表现出早期衰老的表型，其特征是寿命缩短，对90%外显率的广泛肿瘤易感，这表明SUV3是一种新的肿瘤抑制因子。这些疾病表型可以在与野生型雌性小鼠杂交的后代中被拯救，但不能在雄性小鼠中拯救，这表明SUV3的主要作用是通过线粒体介导的。在人类细胞中，SUV3的耗尽会导致截短的线粒体RNA的积累，增加ROS的产生和细胞凋亡。线粒体RNA的降解是一个受到严密监控的过程。在大肠杆菌中，RNase E、Rh1B、PNPase和烯醇化酶是组成降解体的四个主要组分。在哺乳动物中，SUV3和PNPase存在于线粒体中。最近，我们发现SUV3在进化上融合了原始降解体的解旋酶和内切核酸酶的活性，因为SUV3和Rh1B一样，具有解旋酶和ATPase活性，并且像RNaseE一样含有内切核酸酶活性。然而，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。在这一应用中，我们主要针对以下三个方面进行研究：目的1系统研究SUV3杂合子的早衰表型和线粒体功能异常。目的2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是鉴定和鉴定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。与公共卫生相关：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，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。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。

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.