EPIGENETIC REGULATION OF SENESCENCE IN YEAST TELOMERASE MUTANTS

细胞衰老被认为有助于哺乳动物的衰老，并且可以由严重缩短的 从而使端粒脱帽。在人类中，端粒缩短伴随着衰老， 缩短会损害组织内环境稳定的证据。与此同时， 端粒缩短可能限制癌的发生。虽然无帽端粒明显导致检查点 然而，关于细胞对端粒的反应的全部范围和机制， 功能障碍在这里，我们将探讨酵母中端粒脱帽引起的衰老的新方面 端粒酶突变模型，重点是表观遗传变化。将在三个具体目标下对这些问题进行调查： 1)表征衰老过程中糖酵解基因表达的抑制和 存活者对糖酵解因子的影响与端粒沉默因子向内部基因组的明显转移有关 基因座，包括Raplp和sirtuins在这些过程中的作用的阐明，2）研究 在对严重缩短的端粒做出反应时发生的基因表达变化与 具有明显能够形成G-四链体（G4）DNA的序列的启动子，以及3）确定 SUMO化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，酵母提供了一个实验上易于处理的模型，通过 他们经营的。我们将使用已建立的生物化学、分子和细胞生物学方法， 研究蛋白质和基因组DNA序列之间的功能关系，介导 表观遗传变化这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的小分子调节剂在 和Berger博士（项目2）比较染色质修饰的作用 衰老过程中端粒酶突变体与酵母母细胞复制老化。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 旨在治疗与年龄有关的疾病和恶性肿瘤的疗法的未来发展。

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.