Graduation Year

2015

Document Type

Thesis

Degree

M.S.

Degree Name

Master of Science (M.S.)

Department

Biology

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Younghoon Kee, Ph.D.

Committee Member

Kristina Schmidt, Ph.D.

Committee Member

Gary Daughdrill, Ph.D.

Keywords

DNA repair, fanconi anemia, genome instability, homologous recombination, ubiquitin

Abstract

Fanconi anemia (FA) is a genome instability syndrome that is clinically manifested by bone marrow failure, congenital defects, and elevated cancer susceptibility. The FA pathway is known to regulate the repair of DNA interstrand crosslinks in part through DNA homologous recombination (HR) repair. Up to today 16 FA proteins have been discovered that may participate in the common pathway. Cells that have mutations in the FA genes are hypersensitive to DNA damaging agents and display chromosome instability. A key regulatory event in the FA pathway is monoubiquitination of FANCD2-FANCI heterodimer that is mediated by a multi-component E3 ubiquitin ligase complex called FA core complex. Current model suggests that once the FANCD2-FANCI heterodimer is monoubiquitinated it relocates to chromatin where it interacts with other key repair proteins to facilitate DNA repair. More than 90% of the FA cases are presumed to be associated with defects in the monoubiquitination reaction, suggesting the significance of the modification in the pathogenesis of the disease. Despite the significance, the molecular interplay between the FA core complex and the FANCD2-FANCI heterodimer remains enigmatic. We are interested in the assembly mechanism of the various FA subcomplexes into the core complex, and we are actively investigating how the FANCD2-FANCI heterodimer is recruited to these putative subcomplexes. As the FA pathway is a crucial determinant for cellular resistance to DNA damaging agents, there have been hypotheses that disruption of this pathway may be beneficial in enhancing chemosensitivity of certain cancer cells. In collaboration with Dr. Cai’s chemistry lab, we will develop a screen platform to identify a small molecules to interrupt the monoubiquitination reaction. Completion of these studies will enhance the much-needed knowledge of the key enzymatic reaction in the pathway, and perhaps the information can be used for development of novel chemotherapeutic strategies.

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