Chromosome instability (CIN) is a hallmark of many cancer types. Identifying mutations that are synthetic lethal in combination with a CIN phenotype is therefore a promising approach for identifying gene targets for cancer therapeutics. We have previously identified the helicase DOG-1 as the functional ortholog of human FANCJ. When mutated, FANCJ leads to the development of Fanconi Anemia, a hereditary disorder that confers a predisposition to cancer development due to CIN. In C. elegans, the
dog-1 mutant also displays a CIN phenotype arising from deletions that initiate in G-rich DNA. Previous work in our lab has revealed that
dog-1 mutants in combination with mutations in the anti-recombinase
rtel-1 are synthetic lethal. We are currently screening for additional gene products that when non-functional result in lethality specifically in the absence of
dog-1. We have conducted several EMS and X-ray mutagenesis screens designed to assay for somatic cell loss due to synthetic lethality. We have generated 143 potential mutations that we are currently mapping using a combination of traditional mapping techniques and Array Comparative Genomic Hybridization (aCGH). This work will reveal mutations that specifically kill unstable CIN cells in
dog-1 mutant animals. The conserved function of DOG-1 and human FANCJ indicate that the mutated genes we discover are potential therapeutic targets for the specific killing of FANCJ cells in Fanconi Anemia patients. This work is funded by CIHR and MSFHR.