Elucidating the Role of Human FAN1 Nuclease in DNA Crosslink Repair
Fanconi anemia is a childhood disease associated with impaired bone marrow function, developmental retardation, premature aging and early onset of cancer limiting the lifespan of patients to 35 years. Fanconi anemia results from impairment of one or more steps in the preventive pathway that removes aberrant DNA structures, which are caused by environmental stresses like pollutants, toxins in diet, etc.
The major goal of our proposed research is to understand how this preventive pathway repairs DNA, especially the protein component that aids the scission of aberrant DNA region for its removal. Our aim is to understand how this protein component recognizes DNA and how other protein partners coordinate with it. In order to define these mechanistic details, we aim to visually inspect the binding surfaces by solving the crystal structures of these interaction complexes. We also want to discover the DNA structure(s) that is specifically or preferentially recognized by this protein component and efficiently cleaved. We will generate a variety of such aberrant DNA molecules to study binding and cleavage by the protein component. Finally, we will also study how other factors and proteins in the preventive pathway manipulate this protein component. We will do this by probing for direct binding, solving the structures of bound complexes and by inspecting binding surfaces. A detailed molecular understanding of the components of the Fanconi anemia repair pathway and its regulation will also enhance the utility of DNA-damage inducing agents as a guided tool for combinatorial cancer therapy.
"I thank Alex's Lemonade Stand Foundation for choosing to support me during my postdoctoral research pertaining to understanding key steps in the Fanconi anemia pathway of genome maintenance. Fanconi anemia is a cancer prone disorder that greatly limits the lifespan of afflicted children. The overall goal of my research is guiding future therapy by elucidating the mechanism of key steps and reactions involved in Fanconi anemia pathway. I believe that having my own funding support from ALSF will give me greater freedom and independence to focus my research and career goals." - Timsi Rao, PhD