EPIGENETIC REGULATION OF SENESCENCE IN YEAST TELOMERASE MUTANTS

酵母端粒酶突变体衰老的表观遗传调控

• 批准号: 7488201
• 负责人: F. Brad Johnson
• 金额: $ 31.31万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488201
• 关键词: Affinity Chromatography; Age; Aging; Amino Acid Sequence; Apoptosis; Binding; Biochemical; Biological; Cancer Biology; Cell Aging; Cells; Chromatin; Complement Factor B; Complex; DNA; DNA Sequence; Defect; Dependence; Development; Disease; Down-Regulation; Epigenetic Process; Functional disorder; Future; G-Quartets; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic Transcription; Genomics; Glycolysis; Glycolysis Inhibition; Histone H2B; Histones; Homeostasis; Human; Laboratories; Lead; Ligands; Ligase; Link; Malignant Neoplasms; Mammalian Cell; Mammals; Maps; Mediating; Modeling; Modification; Molecular; Mothers; Normal Cell; Pathway interactions; Phenotype; Physiology; Play; Post-Translational Protein Processing; Process; Proteins; Range; Rate; Regulation; Repression; Role; Sirtuins; Small Ubiquitin-Related Modifier Proteins; Speed; Structure; Survivors; Telomerase; Telomere Shortening; Testing; Therapeutic; Thinking; Time; Tissues; Up-Regulation; Yeast Model System; Yeasts; age related; base; cancer cell; carcinogenesis; homologous recombination; inhibitor/antagonist; insight; mutant; programs; promoter; protein expression; response; senescence; small molecule; telomere; transcription factor; tumorigenesis

Cell senescence is thought to contribute to aging in mammals, and can be induced by critically shortened and thus uncapped telomeres. In humans, telomere shortening accompanies aging, and there is increasing evidence that shortening impairs tissue homeostasis. At the same time, limited proliferation caused by telomere shortening may limit carcinogenesis. Although uncapped telomeres clearly lead to checkpoint responses, questions remain concerning the full range and mechanisms of cellular responses to telomere dysfunction. Here we will investigate new aspects of senescence caused by telomere uncapping in a yeast telomerase mutant model, focusing on epigenetic changes. These will be investigated in three specific aims: 1) Characterize the inhibition of glycolytic gene expression during senescence and the dependence of survivors on glycolytic factors related to an apparent shift of telomere silencing factors to internal genomic loci, including elucidation of the roles of Raplp and sirtuins in these processes, 2) Investigate the relationship between gene expression changes that occur in response to critically shortened telomeres and promoters having sequences with the apparent capacity to form G-quadruplex (G4) DNA, and 3) Determine roles for SUMOylation in regulating the rates of senescence and formation of survivors of senescence. Each of these epigenetic changes has been linked to cell senescence, telomere function, aging and cancer biology in humans, and yeast provides an experimentally tractable model in which to dissect the mechanisms by which they operate. We will use established biochemical, and molecular and cell biological approaches to investigate the functional relationship between the proteins and genomic DNA sequences that mediate the epigenetic changes. All three aims will make extensive use of the Program Cores. In addition, we will collaborate with Dr. Marmorstein (Project 1) to test the effects of small molecule regulators of sirtuins during senescence and in survivors, and with Dr. Berger (Project 2) to compare the roles of chromatin modifications during senescence of telomerase mutants with yeast mother cell replicative aging. Understanding how these epigenetic changes regulate the physiology of cell senescence will offer new insights into aging and cancer biology. Together with the other projects in the program, these studies will provide new targets for the future development of therapeutics aimed at treating age-related diseases and malignancies.

细胞衰老被认为是导致哺乳动物衰老的原因之一，并且可以通过细胞寿命的严重缩短来诱导。 因而端粒无帽。在人类中，端粒缩短伴随着衰老，而且这种现象正在增加 有证据表明缩短会损害组织稳态。与此同时，有限的扩散 端粒缩短可能会限制致癌作用。尽管无帽端粒明显导致检查点 尽管细胞对端粒反应的全部范围和机制仍然存在疑问 功能障碍。在这里，我们将研究酵母中端粒脱帽引起的衰老的新方面 端粒酶突变模型，重点关注表观遗传变化。这些将针对三个具体目标进行调查： 1) 表征衰老过程中糖酵解基因表达的抑制及其依赖性 与端粒沉默因子明显转移到内部基因组相关的糖酵解因子的幸存者 位点，包括阐明 Raplp 和 Sirtuins 在这些过程中的作用，2) 研究 响应端粒严重缩短而发生的基因表达变化之间的关系 具有具有形成 G-四链体 (G4) DNA 的表观能力的序列的启动子，以及 3) 确定 SUMOylation 在调节衰老速率和衰老幸存者形成中的作用。每个 这些表观遗传变化与细胞衰老、端粒功能、衰老和癌症生物学有关 在人类中，酵母提供了一种实验上易于处理的模型，可以通过以下方式剖析其中的机制： 他们经营的。我们将使用已建立的生化、分子和细胞生物学方法来 研究介导蛋白质和基因组 DNA 序列之间的功能关系 表观遗传变化。所有三个目标都将广泛使用程序核心。此外，我们将 与 Marmorstein 博士（项目 1）合作，测试 Sirtuins 小分子调节剂在 衰老和幸存者，并与 Berger 博士（项目 2）比较染色质修饰的作用 在端粒酶突变体随着酵母母细胞复制衰老而衰老的过程中。了解如何 这些表观遗传变化调节细胞衰老的生理学将为衰老和衰老提供新的见解。 癌症生物学。与该计划中的其他项目一起，这些研究将为 旨在治疗与年龄相关的疾病和恶性肿瘤的疗法的未来发展。