SIRT6 role in facilitating more efficient genome and epigenome maintenance in long-lived species.

SIRT6 在促进长寿物种更有效地维持基因组和表观基因组方面发挥着作用。

• 批准号: 10152477
• 负责人: Vera Gorbunova
• 金额: $ 38.83万
• 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: 2014-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152477
• 关键词: ADP ribosylation; ATAC-seq; Address; Age; Aging; Amino Acid Substitution; Amino Acids; Animals; Automobile Driving; Balaena; Beavers; CRISPR/Cas technology; Cells; Collaborations; Collection; DNA Damage; DNA Double Strand Break; DNA Methylation; DNA Repair; DNA Sequence Rearrangement; DNA Transposable Elements; Data; Deacetylation; Dose; Double Strand Break Repair; Engineering; Epigenetic Process; Evolution; Fibroblasts; Funding; Gene Expression Profile; Genes; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Health; Histones; Human; Hyaluronan; Intervention; Longevity; Maintenance; Malignant Neoplasms; Mammals; Maps; Mass Spectrum Analysis; Massive Parallel Sequencing; Metabolism; Methylation; Modification; Mole Rats; Mouse Protein; Mus; Phenotype; Play; Process; Proteins; Research; Rodent; Role; Sampling; Site; Squirrel; Structure; Testing; Variant; Work; aged; base; blind; comparative; comparative genomics; epigenome; epigenomics; gamma irradiation; healthspan; improved; insight; metabolome; methylome; overexpression; prevent; resilience; senescence; stability testing; tool; transcriptome

SUMMARY: The long-term goal of Project 1 is to identify mechanisms responsible for more efficient genome and epigenome maintenance in long-lived animal species. Genome instability, including genomic rearrangements arising from errors during repair of DNA breaks, and dysregulation of epigenetic landscapes are believed to be contributing causes of aging. In the current period of support, we demonstrated that the efficiency of DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), correlates positively with maximum lifespan. Furthermore, we demonstrated that SIRT6 protein, which serves as an upstream regulator of DSB repair, is a major factor responsible for the differences in DSB repair efficiency between species. SIRT6 ability to promote DSB repair correlated strongly with maximum lifespan. By dissecting SIRT6 sequence variation across rodents with large differences in lifespan, we identified five amino acids fully responsible for the differences in SIRT6 activity in promoting DSB repair, as well as the differences in SIRT6 deacetylation and mono-ADP-ribosylation activities. Other preliminary studies identified SIRT6 as a key factor in epigenome stability during aging. We found that SIRT6 suppresses activation of transposable elements in aged mice, restores inducibility of NRF2 target genes, and confers more youthful expression signatures to senescent cells. Based on these findings, our objectives are to expand our analysis of SIRT6 changes responsible for improved DSB repair to other long-lived species; test whether long-lived species have more stable epigenome maintenance upon DNA damage and characterize the role of SIRT6 in this process; and finally, test whether the identified five amino acid changes that improve mouse SIRT6 to the level found in long-lived species result in lifespan extension. Our overarching hypothesis is that longevity is associated with improved DSB repair and epigenome maintenance and stimulation of SIRT6 activity can improve these processes and extend the lifespan. We propose to: (1) Integrate data from multiple long-lived species to determine the landscape of amino acid changes in SIRT6 that are associated with longevity and improved DSB repair; (2) Test whether the ability to recover epigenome organization following DNA damage correlates with maximum lifespan, and identify the role of SIRT6 in this process. We will collaborate with Project 2 to test the effect of hyaluronan on epigenome maintenance, and with Project 3 to compare genome and epigenome maintenance in different rodent species upon DNA damage. (3) Construct a “beaverized” SIRT6 mouse containing five beaver amino acid substitutions responsible for enhanced SIRT6 activity and with Core C test whether these mice show improved health and lifespan. We will work with Project 3 to characterize genome and epigenome stability in these mice and with Project 4 to determine whether improved DNA repair in these mice results in more youthful metabolism and methylation age. The proposed research will identify targets for interventions aimed at promoting genome and epigenome stability and extending lifespan.

摘要：项目 1 的长期目标是确定负责更高效基因组的机制 和长寿动物物种的表观基因组维持。基因组不稳定，包括基因组 DNA 断裂修复过程中的错误引起的重排以及表观遗传景观的失调 被认为是导致衰老的原因。在当前的支持期间，我们证明了效率 DNA 双链断裂 (DSB) 修复（而非核苷酸切除修复 (NER)）与 最大使用寿命。此外，我们还证明了 SIRT6 蛋白作为上游调节因子 DSB 修复的效率是造成物种间 DSB 修复效率差异的一个主要因素。 SIRT6 促进 DSB 修复的能力与最大寿命密切相关。通过剖析 SIRT6 序列变异 在寿命差异较大的啮齿类动物中，我们确定了五种氨基酸，它们完全负责 SIRT6 活性在促进 DSB 修复方面的差异，以及 SIRT6 去乙酰化和 单-ADP-核糖基化活性。其他初步研究确定 SIRT6 是表观基因组的关键因素 老化过程中的稳定性。我们发现 SIRT6 抑制老年小鼠转座元件的激活， 恢复 NRF2 靶基因的诱导能力，并赋予衰老细胞更年轻的表达特征。 基于这些发现，我们的目标是扩大对 SIRT6 变化的分析，这些变化负责改进 对其他长寿物种的 DSB 修复；测试长寿物种是否具有更稳定的表观基因组 维持 DNA 损伤并表征 SIRT6 在此过程中的作用；最后，测试是否 确定了五种氨基酸变化，可将小鼠 SIRT6 提高到长寿物种的水平，从而导致 寿命延长。我们的首要假设是长寿与 DSB 修复的改善和 表观基因组的维持和 SIRT6 活性的刺激可以改善这些过程并延长寿命。 我们建议：（1）整合多个长寿物种的数据以确定氨基酸的分布 SIRT6 的变化与寿命和 DSB 修复的改善相关； (2)测试是否有能力 DNA 损伤后恢复表观基因组组织与最大寿命相关，并确定其作用 SIRT6 在此过程中的作用。我们将与项目2合作测试透明质酸对表观基因组的影响 维护，并与项目 3 比较不同啮齿动物物种的基因组和表观基因组维护 DNA损伤后。 (3)构建含有5个海狸氨基酸取代的“海狸化”SIRT6小鼠 负责增强 SIRT6 活性，并使用 Core C 测试这些小鼠是否表现出健康状况改善和 寿命。我们将与 Project 3 合作来表征这些小鼠的基因组和表观基因组稳定性，并 项目 4 旨在确定这些小鼠 DNA 修复的改善是否会导致更年轻的新陈代谢和 甲基化年龄。拟议的研究将确定旨在促进基因组和 表观基因组稳定性和延长寿命。