Role of stress pathways in alternative lengthening of telomeres

在没有端粒酶的情况下，端粒随着细胞的每次分裂而缩短，导致细胞周期停滞和衰老。替代延长端粒(ALT)可以通过促进一种形式的端粒酶非依赖性端粒重复增加来拯救细胞免于这种命运。ALT被发现是所有癌症类型中10%的细胞增殖的主要原因。在缺乏端粒酶逆转录酶亚基TRT-1的线虫突变体中，端粒每代都会缩短。虽然在最佳条件下生长的TRT-1突变体在大约20-30代后变得不育，但在应激条件下(如拥挤、饥饿)生长的TRT-1蠕虫可以通过ALT无限期存活，这表明应激反应途径和端粒生物学之间存在相互作用。为了研究应激对ALT的影响，我将定义以下目标。目的1：为了确定应激是否能促进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在没有拥挤和饥饿的情况下变为ALT。目的2：同时，一个对酒精作出反应的基因以及酒精本身将被测试，以研究另一种与拥挤和饥饿反应无关的应激途径，这可能与ALT的激活有关。目标3：最后，我将研究应激途径如何导致ALT。

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.