Mechanistic Dissection of the Fanconi Anemia Pathway of DNA Damage Response and R

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DESCRIPTION (provided by applicant): Fanconi anemia (FA) is a multigenic disorder marked by progressive bone marrow failure and a strong cancer predisposition. Numerous studies have linked mutations in FA genes to familial breast, pancreatic, and other cancers, and have also provided ample evidence to implicate silencing of FA genes in the etiology of sporadic cancers. FA cells are hypersensitive to radiation and other DNA damaging agents, DNA crosslinking chemicals in particular, prone to DNA replicative stress, and exhibit chromosome fragility. These phenotypic manifestations stem from defects in DNA damage signaling and repair, and FA protein functional and physical interactions have indicated an important link to the familial breas cancer proteins BRCA1 and BRCA2. The involvement of the FA/BRCA-dependent DNA damage response in cancer suppression underscores the need to understand the mechanistic underpinnings of this genome maintenance pathway. In this project, we will employ a combination of biochemical and in vivo approaches to test hypotheses regarding the manner by which protein-protein and protein-DNA interactions involving key FA and partner proteins mediate the post-translational modifications of the FANCI-FANCD2 complex and also the homology-directed repair of damaged DNA. The success of this project is assured by the complementary expertise of the two participating Yale groups, led by Dr. Patrick Sung and Dr. Gary Kupfer, and an exceptionally strong collaborative framework within the broader Yale community. These attributes help ensure that findings of the highest possible impact will be obtained. Since the biology of FA intersects with cancer biology in general, our project promises to shed light on critical processes of genomic surveillance as well as common themes of oncogenesis. We expect our studies to yield insight into common pathways of cancer and to identify novel targets for manipulation in cancer therapy.