MECHANISTIC DISSECTION OF THE FALCONI ANEMIA PATHWAY OF DNA DAMAGE RESPONSE AND REPAIR

Proteins from the Fanconi anemia (FA) pathway play an integral role in DNA repair by homologousrecombination (HR). FA is a multigenic disorder marked by progressive bone marrow failure and astrong 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 FAgenes in the etiology of sporadic cancers. FA cells are hypersensitive to radiation and other DNAdamaging agents, DNA crosslinking chemicals and reactive aldehydes in particular, prone to DNAreplicative stress, and exhibit chromosome fragility. These phenotypic manifestations stem fromdefects in DNA damage signaling and repair, and FA protein functional and physical interactions haveindicated an important link to the familial breast cancer proteins BRCA1 and BRCA2. Theinvolvement of the FA/BRCA-dependent DNA damage response in cancer suppression underscoresthe 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 the novelhypotheses that the FA pathway coordinates the prevention and resolution of genotoxic structuresresulting from aberrant transcription events and HR. Aim 1 will focus on the mechanism whereby theID2 complex and UAF1-containing complexes engage nucleic acid containing structures and activateHR. Aim 2 will explore how the FANCM-BLM axis resolves pathogenic RNA containing and othernucleic acid intermediates in a way that regulates HR activities. The success of this project isassured by the complementary expertise of the two participating Yale groups, led by Dr Patrick Sungand Dr Gary Kupfer, and an exceptionally strong collaborative framework within the broader Yalecommunity. In addition, the PIs have enlisted two investigators, Dr. Claudia Wiese and Dr. AndresAguilera, whose expertise will even more elegantly allow the team to interrogate this novel area ofgenomic instability. These attributes help ensure that findings of the highest possible impact will beobtained. Since the biology of FA intersects with cancer biology in general, our project promises toshed 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 targetsfor manipulation in cancer therapy.