Elucidating the Initiation Mechanism of the Fanconi Anemia Pathway of DNA Damage Repair

Fanconi anemia (FA) is a childhood disease characterized by multiple devastating symptoms, which include bone marrow failure leading to aplastic anemia, congenital abnormalities, and a high incidence of cancer. Although recent medical advances have increased the life expectancy for FA patients, they often succumb to tumor malignancies before reaching adulthood. Therefore, research into the cellular and molecular basis of FA-associated cancer is urgently needed.

 
The research outlined in this application builds on recent evidence that the proteins mutated in FA constitute a novel DNA repair network whose genetic inactivation represents the underlying molecular basis of the disease. Critical FA proteins orchestrate the formation of a large multiprotein complex on damaged DNA that leads to damage repair. However, the structural and biochemical interactions that govern the interplay between the FA pathway and DNA damage response are not fully understood.
 
The long-term goal of our research is to establish the structural principles of the crosstalk between the FA pathway and the DNA repair machinery. Toward this goal we will perform biochemical studies of critical FA proteins, identify their interaction complexes, and determine their crystal structures. Our initial focus will be on well-defined systems with a high likelihood of success in the projected funding period. These data will then form the basis for subsequent studies involving systems of higher complexity. Information gained from our endeavors may lead to improved anticancer treatment to alleviate the sufferings of children with FA, and possibly a broader population of children afflicted with cancer.