Grant: Fellowship - Priority Announcement: Fanconi Anemia (SHOPP)

Fanconi Anemia (FA) is a devastating disorder associated with increased cancer susceptibility. FA patients will often develop anemia and cancer. FA is caused by mutations in DNA repair system, specifically the interstrand crosslink (ICL) repair. Currently, 15 human genes have been associated with FA. The initiation of the pathway has been well studied, but many of the repair mechanisms after the initiation are not well understood. The model organism Caenorhabditis elegans has been instrumental in understanding the function of FA components. So far, seven FA genes have been identified in C. elegans, including dog-1 as FANCJ. Due to the highly parallel DNA repair system between C. elegans and humans, I want to further develop C. elegans as a model system for studying FA. I will first identify other FA genes in C. elegans using bioinformatics and genomics methods. The Rose lab has hundreds of uncharacterized mutant strains enriched in DNA repair genes. We may find additional FA genes in this library by identifying their molecular identity in a high throughput manner. The ultimate goal of my research project is to understand the genomic consequences when FA pathway is lost. To accomplish this, I will employ next-generation sequencing technology to sequence and classify the types of mutational changes in mutator strains that have lost FA components. Whole genome sequence will provide a global picture the types of mutation that can accumulate over time. Using the same technology, I will examine the genomic sequences of strains treated with crosslinking agents, such as the common chemotherapy agent mitomycin C, to classify genomic alterations in response to mutagens. Results from my research will give us a better understanding the relationship between mutators and ICL and will help develop therapeutics for FA derived cancers.