Mutant p53 Together with Gain-of-Function GLP-1/Notch Decreases UVC-Damage-Induced Germline Cell Death but Increases PARP Inhibitor-Induced Germline Cell Death.

The gene is mutated in over 50% of human cancers, and the gene encodes the ortholog CEP-1. CEP-1 is activated by ultraviolet type C (UVC)-induced DNA damage and activates genes that induce germline apoptosis. UVC treatment of gain-of-function tumorous animals reduces germline stem cell numbers (and overall tumor size), while UVC treatment of double-mutant increases DNA damage adducts and stem cell tumor volume. We compared UVC-induced mitotic stem cell death and animal lifespans for the two different tumorous strains. stem cell compartment death has never been observed, and we used engulfed small stem cells, notable by green fluorescent puncta, to count cell death events. We found UVC treatment of animals increased stem cell death and increased lifespan. However, UVC treatment of double-mutant animals decreased stem cell death, increased tumor volume, and decreased animal lifespan. There are pharmacological agents that induce p53-independent cell death of human cells in culture; and two notable protocols are the PARP-trapping agents of temozolomide plus talazoparib and the nucleoside analogue 8-amino-adenosine. It is important to determine ways to rapidly test for pharmacological agents able to induce p53-independent cell death. We tested feeding nematodes with either 8-amino-adenosine or temozolomide plus talazoparib and found both were able to decrease tumor volume. This is the first comparison for p53-independent responses in animals and showed UVC DNA damage increased tumor volume and decreased lifespan while PARP inhibition decreased tumor volume.