Role of stress pathways in alternative lengthening of telomeres

应激途径在端粒选择性延长中的作用

• 批准号: 359310694
• 负责人: Dr. Maya Spichal
• 金额: --
• 依托单位: Department of Genetics
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/359310694?language=en
• 关键词: Role; stress; pathways; alternative; lengthening

In the absence of telomerase, telomeres shorten with every cell division leading to cell cycle arrest and senescence. Alternative lengthening of telomeres (ALT) can rescue cells from this fate by promoting a form of telomerase-independent telomere repeat addition. ALT was found to be the primary cause of cell proliferation in 10% of all cancer types. In C. elegans mutants deficient for the telomerase reverse transcriptase subunit trt-1, telomeres shorten every generation. While trt-1 mutants grown under optimal conditions become sterile after about 20-30 generations, trt-1 worms grown under stressful conditions (e.g. crowding, starvation) can survive indefinitely via ALT, suggesting an interaction between stress response pathways and telomere biology. In an approach to study the influence of stress on ALT I will define the following aims.Aim 1: To determine if stress can promote ALT, I will use mutants of different stress pathways in trt-1 worms to test if they become ALT even when crowding and starvation are absent. Aim 2: In parallel, a gene that responds to alcohol, as well as alcohol itself, will be tested to study an alternative stress pathway that is not involved in the response to crowding and starvation, that may be relevant to activation of ALT. Aim 3: Finally, I will study how stress pathways could lead to ALT.

在没有端粒酶的情况下，端粒随着每次细胞分裂而缩短，导致细胞周期停滞和衰老。选择性端粒延长（ALT）可以通过促进一种非端粒酶依赖性端粒重复序列的添加来拯救细胞。ALT被发现是10%的所有癌症类型中细胞增殖的主要原因。In C.在端粒酶逆转录酶亚基trt-1缺陷的线虫突变体中，端粒每一代都会缩短。虽然在最佳条件下生长的trt-1突变体在约20-30代后变得不育，但在应激条件下（例如拥挤、饥饿）生长的trt-1蠕虫可以通过ALT无限期地存活，这表明应激反应途径和端粒生物学之间存在相互作用。在研究应激对ALT影响的方法中，我将定义以下目标：目的1：为了确定应激是否会促进ALT，我将使用trt-1蠕虫中不同应激途径的突变体来测试它们是否即使在没有拥挤和饥饿的情况下也会成为ALT。目标二：与此同时，将测试对酒精以及酒精本身作出反应的基因，以研究不参与对拥挤和饥饿的反应的替代应激途径，这可能与ALT的激活有关。目标3：最后，我将研究压力途径如何导致ALT。