Erica Bogan, Ekaterini A. Kritikou1, Michael O. Hengartner1. Apoptosis, or programmed cell death, is a complex process of cellular self-destruction. Programmed cell death has been extensively studied in C. elegans because it is an intrinsic, reproducible part of the developmental program in both the soma and the germ line of the worm. Several different, genetically separable pathways that lead to germ cell apoptosis have so far been described. These include a DNA damage pathway, induced by genotoxic stress, which results in the induction of germ cell apoptosis and mitotic germ cell cycle arrest.. The tumor suppressor protein
p53 has a key role in the integration of cellular responses to genotoxic stimuli, by inducing either cell cycle arrest or apoptosis following DNA damage. Like its mammalian homolog, the C. elegans
p53 protein, CEP-1, is required for DNA damage-induced germ cell apoptosis, but it appears to be dispensable for cell cycle arrest after exposure to ionizing radiation..
ape-1 encodes a
p53/CEP-1-binding protein conserved from worms to humans, which apparently inhibits
p53/CEP-1 in the absence of genotoxic stress.
ape-1(lf) mutants have increased germline apoptosis (Gla phenotype) that is
p53/CEP-1-dependent. These worms also have other defects associated with DNA damage checkpoints: although the mitotic germ cells have a normal cell cycle arrest response induced by IR, the apoptotic response is defective. We are currently pursuing the biochemical characterization of APE-1 and its interaction with CEP-1, as well as genetic studies with
ape-1(lf) mutants that will hopefully shed light on the mechanism through which APE-1 functions and how it interacts with the C. elegans
p53 homologue CEP-1. We also hope this study will help us unravel the responses triggered by DNA damage that have been conserved from worms to humans.