Role of stress pathways in alternative lengthening of telomeres

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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.