Regulation of genome stability by SITR6

SITR6 对基因组稳定性的调节

• 批准号: 9214301
• 负责人: Andrei Seluanov
• 金额: $ 31.47万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214301
• 关键词: ADP ribosylation; Affect; Age of Onset; Aging; Aging-Related Process; Amino Acids; Animals; Attenuated; Binding; Biological Assay; Cardiac; Cell physiology; Chromatin; Chromosome abnormality; DNA; DNA Double Strand Break; DNA Repair; DNA Repair Gene; DNA Transposable Elements; DNA-dependent protein kinase; Data; Disease; Double Strand Break Repair; Etiology; Genes; Genome; Genome Stability; Genomic Instability; Glycolysis; Goals; Health; Histone Deacetylase; In Vitro; Inflammation; Knock-in Mouse; L1 Elements; Laboratories; Lead; Life; Link; Longevity; MAPK8 gene; Malignant Neoplasms; Mobile Genetic Elements; Modification; Molecular; Mono(ADP-Ribose) Transferases; Mono-S; Mus; Mutation; Oxidative Stress; Pathology; Pathway interactions; Phenotype; Phosphorylation; Phosphorylation Site; Play; Population; Positioning Attribute; Post-Translational Protein Processing; Prevention; Proteins; Regulation; Regulatory Pathway; Repetitive Sequence; Repression; Research; Retrotransposition; Retrotransposon; Role; Signal Transduction; Sirtuins; Site; Stress; Sulfur; Telomere Maintenance; Testing; Therapeutic; age related; design; experimental study; improved; in vivo; insight; interest; mimetics; mouse model; mutant; novel; novel strategies; overexpression; promoter; public health relevance; repaired; response; telomere; tumorigenesis

DESCRIPTION (provided by applicant): The long-term goal of this project is to define the molecular mechanisms which regulate the activity of the mammalian sirtuin, SIRT6, especially in the context of genome stability. Additionally, the studies outlined in this proposal will delineate the relevance of these regulatory controls in regards to aging and the onset of age- related disease. SIRT6 has emerged as a critical regulator of multiple pathways related to aging, including DNA repair, telomere maintenance, tumorigenesis, inflammation and glycolysis. Moreover, it has been demonstrated that SIRT6 overexpression extends the lifespan of mice. Despite the overwhelming evidence that SIRT6 operates at the crux of multiple pathways related to aging, very little is known about the upstream regulatory mechanisms which control the activity of SIRT6 and allow it to regulate such a diverse array of cellular processes. In this application we propose to identify the regulatory pathways that control the activity of SIRT6; in particular, we will focus on understanding the mechanisms that regulate the activity of SIRT6 in the context of genome stability. Recent studies by our laboratory demonstrated that SIRT6 is an upstream regulator of DNA double strand break (DSB) repair. We showed that SIRT6 stimulates both pathways of DSB repair under oxidative stress. Our unpublished preliminary data shows that SIRT6 is phosphorylated by JNK1/2 in response to oxidative stress on amino acid S10 and that this phosphorylation is required for the stimulation of DSB repair. We have also shown that, in addition to controlling DSB repair, SIRT6 maintains genome stability by repressing transposable elements, and that oxidative stress causes re-localization of SIRT6 from the promoters of transposable elements to the sites of newly formed DNA breaks. Thus, we are ideally positioned to conduct further mechanistic studies of SIRT6 regulation in the context of genome stability. As such, we will pursue the following specific aims: (1) identify the mechanisms which regulate the ability of SIRT6 to stimulate DNA repair in response to oxidative stress; (2) identify the mechanisms which regulate the ability of SIRT6 to suppress expression of LINE-1 retrotransposons; and (3) determine the role of SIRT6 phosphorylation in genome stability and longevity by constructing mouse models with mutations in the SIRT6 phosphorylation sites. The proposed research will provide novel and important insights into the regulatory mechanisms, which govern SIRT6 activity as well as delineate new pathways regulated by SIRT6 which are relevant to genome stability and aging. As such, we expect that these experiments will reveal critical, new information about the aging process, and will help to develop novel strategies for treating age-related diseases, in particular diseases of genome instability such as cancer.

描述（由申请人提供）：该项目的长期目标是定义调节哺乳动物Sirtuin，Sirt6活性的分子机制，尤其是在基因组稳定性的背景下。此外，该提案中概述的研究将描述 这些监管控制在衰老和与年龄相关疾病的发作方面的相关性。 SIRT6已成为与衰老有关的多种途径的关键调节剂，包括DNA修复，端粒维持，肿瘤发生，炎症和糖酵解。此外，已经证明SIRT6过表达延长了小鼠的寿命。 尽管有大量证据表明SIRT6在与衰老有关的多种途径的关键中运行，但对控制SIRT6活性的上游调节机制知之甚少，并允许其调节如此多样的细胞过程。在此应用程序中，我们建议确定控制SIRT6活性的监管途径；特别是，我们将专注于理解在基因组稳定性背景下调节SIRT6活性的机制。 我们的实验室最近的研究表明，SIRT6是DNA双链断裂（DSB）修复的上游调节剂。我们表明，在氧化应激下，SIRT6刺激DSB修复的两种途径。我们未发表的初步数据表明，SIRT6响应于氨基酸S10的氧化应激而被JNK1/2磷酸化，并且这种磷酸化是刺激DSB修复所必需的。我们还表明，除了控制DSB修复外，SIRT6还通过抑制转座元件来保持基因组稳定性，并且氧化应激导致SIRT6从转座元素的启动子重新定位到新形成的DNA断裂的位点。因此，理想情况下，我们可以在基因组稳定性的背景下对SIRT6调节进行进一步的机械研究。因此，我们将追求以下特定目的：（1）确定调节SIRT6刺激DNA修复能力的机制； （2）确定调节SIRT6抑制线路1逆转座子表达能力的机制； （3）通过在SIRT6磷酸化位点构造突变的小鼠模型来确定SIRT6磷酸化在基因组稳定性和寿命中的作用。 拟议的研究将提供有关调节机制的新颖和重要的见解，该机制控制了SIRT6活性以及划定由SIRT6调节的新途径，这些途径与基因组稳定性和衰老有关。因此，我们预计这些实验将揭示有关衰老过程的关键，新信息，并有助于制定治疗与年龄相关疾病的新型策略，特别是癌症等基因组不稳定性疾病。