The majority of current cancer treatments, which include radiotherapy and most chemotherapies, elicit cancer cell death through the induction of excessive DNA damage, the premise being that defects in the DNA damage response (DDR) pathway make cancer cells more susceptible to the lethal effects of DNA damage. However, mutations in the DDR pathway that hinder DNA-damage induced apoptosis, such as those that impair the pro-apoptotic tumor suppressor p53 or upregulate the anti-apoptotic oncogene Bcl-2, can also form the basis for resistance to cancer therapy. The goal of the Jette Lab is to discover therapeutic targets whose inhibition restores normal cell death pathways to cancer cells that are resistant to DNA-damaging agents. Using a forward genetic approach, we have identified a number of recessive mutations that give rise to radiosensitization phenotypes during zebrafish development. These mutations re-sensitize bcl-2-overexpressing cells to pro-apoptotic stimuli, and importantly, they represent genes with novel roles in the DDR pathway. We are currently dissecting the function of these genes in the DDR pathway through genetic epistasis analysis in zebrafish embryos, biochemical analysis in human cell culture, and ability of the mutations to sensitize bcl-2-overexpressing zebrafish T-cell tumors to radiation-induced apoptosis.