DNA Damage and Repair

Role of FAN1 in FA pathway of interstrand crosslink repair

Fanconi anemia (FA) is an inherited, cancer-prone disorder associated with impaired bone marrow function leading to lowered production of blood cells. At the molecular level, FA is characterized by a failure to remove interstrand DNA crosslinks (ICLs) from damaged chromosomes. Fanconi anemia-associated nuclease 1 (FAN1) is a component within the FA repair-pathway core complex that repairs ICLs by facilitating translesion synthesis and homologous recombination. To understand the mechanism by which FAN1 brings about the efficient cleavage of target ICL DNA, we structurally and functionally characterize the specificity determinants of FAN1-DNA binding and cleavage, in isolation and as part of higher order multi-protein assembly subcomplexes of the FA pathway. Understanding the biological function and mechanism of the Fanconi anemia pathway proteins has strong relevance for therapeutic intervention for this disease treatment as well as cancer etiology, as the high cytotoxicity of aberrant DNA makes the intentional introduction of chemical agents that produce such lesions a valuable regimen for the selective killing of cancerous cells.

BRCA1/BARD1 in homologous recombination

Breast cancer is one of the most common cancers in women world over, with 5% of these cases being attributed to mutations in the BRCA1 gene. Since BRCA1 plays a key role in genome maintenance pathways, its deficiency leads to genetic instability and ultimately to the cancer phenotype1. Studies by many groups done over the past two decades have provided compelling evidence for an involvement of BRCA1 in homologous recombination (HR), which is one of a key pathway for the repair of chromosomes that harbor DNA doublestrand breaks (DSBs). From recognition of a DSB to completion of error-free repair, HR requires the interplay of numerous interacting partners and BRCA1, being a large protein, acts as a scaffold for many of the HR associated effector proteins for complex assembly and regulation. We aim to structurally characterize the BRCA1/BARD1 complex and it higher order assemblies to expand our molecular understanding of BRCA1 and its associated factors in chromosome damage repair. This will enable a structure-based small molecule design to modulate BRCA1 and homologous recombination activities in cells.