Richard Kolesnick: Radiation Response Genes in the Worm Caenorhabditis elegans

For the last decade, our laboratory has been evaluating conserved gene functions and their genetic interactions after ionizing radiation using the nematode C. elegans. In many instances where mammalian systems are too complicated to obtain clear information concerning signaling pathways, C. elegans has been instructive. Mammalian systems often have multiple isoforms of an enzyme; whereas C. elegans may possess a single form. Further, mammalian tissue diversity has many times resulted in the utilization of signaling proteins in a combinatorial manner. The simplicity of the C. elegans system coupled with the capacity to readily incorporate more than 1 mutated allele in a single animal make this model ideal for asking questions regarding the molecular ordering of signaling cascades.

Our laboratory has focused on several gene pathways involved in the sensing of radiation damage and the signaling of apoptotic and post-mitotic (reproductive) death in germ line. In our previous studies we identified C. elegans ABL-1, the homolog for human c-Abl and demonstrate that ABL-1 plays an anti-apoptotic role in the C. elegans germ line by acting as a negative regulator of the p53 homolog CEP-1 (Nature Genetics, 2004). Subsequently we characterized 24 genetic mutants of the C. elegans sphingolipid metabolic pathway. We initially defined CEP-1/p53-mediated EGL-1 up-regulation and ceramide synthase-mediated ceramide generation on parallel pathways that integrate at mitochondrial membranes to co-regulate the stress-induced apoptotic checkpoint (Science, 2008). We are in the process of screening genes involved in ionizing radiation-induced DNA repair using a C. elegans germ line tumor model. Data to date indicate specific relevance of the homologous recombination DNA repair apparatus in potential therapy for Notch driven tumor stem cell lethality.