In the absence of telomerase telomeres shorten with very cell division leading to cell cycle arrest and senescence. Alternative lengthening of telomeres (ALT) can rescue cells from their proliferation arrest and was found to be the primary cause in 10% of all cancer types.
In C. elegans deficient for the telomerase reverse transcriptase subunit trt-1, telomeres shorten every generation affecting germline cells with little or no effect on somatic cells or lifespan (1, 2). While trt-1 worms grown under optimal conditions become sterile after about 20 generations, trt-1 worms grown under stressful conditions can survive indefinitely via ALT, suggesting an interaction between stress response pathways and telomere biology (3).
Additionally, telomere shortening could activate stress pathways long before complete telomere attrition as various forms of DNA damage were shown to trigger an innate immune response in C. elegans (4).
Under stressful conditions worms can develop into stress resistant dauer larvae to promote survival. Here we address two of the four dauer arrest stress response pathways. Preliminary results indicate that deficiency for telomerase in conjunction with deficiency for either the TGF-b or the lifespan extending insulin/IGF pathway may each lead to distinct synthetic interactions that could be generally relevant to deficiency for telomerase in the context of aging or cancer.
1) Meier B, Clejan I, Liu Y, Lowden M, Gartner A, Hodgkin J, Ahmed S (2006) trt-1 Is the Caenorhabditis elegans Catalytic Subunit of Telomerase. PLoS Genet 2(2): e18
2) Raices M, Maruyama H, Dillin A, Karlseder J (2005) Uncoupling of Longevity and Telomere Length in C. elegans. PLoS Genet 1(3): e30
3) Cheng C, Shtessel L, Brady M, Ahmed S (2012) Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths. PNAS 109(20):7805-10
4) Ermolaeva MA, Segref A, Dakhovnik A, Ou HL, Schneider JI, Utermohlen O, Hoppe T, Schumacher B (2013) DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501: 416-420.