Research Interest: DNA Damage, Cancer, and Neurodegeneration
Our research is centered on two different areas:
studies of the mechanisms underlying cellular responses to DNA damage and the maintenance of genomic stability;
- characterization of molecular processes of neurodegenerative disorders that result from toxic protein accumulation. Our studies employ a combination of approaches in molecular biology, genetics, biochemistry, cell biology, and functional genomics.
DNA Damage Checkpoint and Genomic Stability
Uncontrolled cell proliferation, a hallmark of cancer, results from accumulation of DNA damage and the ensuing genomic instability. Cells have evolved surveillance mechanisms (i.e. checkpoints) to monitor genome integrity during the normal cell cycle and in response to genotoxic stress. Elucidation of these regulatory mechanisms will provide a molecular basis for cancer diagnosis, prevention, and treatment. We are currently studying S. cerevisiae genes encoding ribonucleotide reductase (RNR), a evolutionarily conserved enzyme that is required for de novo synthesis of deoxyribonucleotides (dNTPs). Because of the essential role of RNR in both DNA replication and DNA repair, it has been under intensive investigation as a potential target for cancer intervention. We have recently shown that the subcellular localization of the RNR subunits is regulated by the DNA damage checkpoint. Our results suggest a new mechanism of optimizing cellular levels of dNTP synthesis for repairing DNA lesions. We want to understand the molecular basis of such DNA damaged-induced redistribution and its physiological implication, with the ultimate aim of uncovering novel molecular targets for RNR inhibition and cancer therapy.
One other area of our current research is on how cellular dNTP pool levels affect mitochondrial genome stability. Mutations in the mitochondrial genome have been implicated in a large number of human genetic disorders. Our long-term goal in this area of research is to gain further insight into the interaction between nuclear DNA processes such as replication and repair and mitochondrial genome maintenance.
Genetic Models of Neurodegenerative Disorders
Many neurodegenerative disorders are characterized by protein aggregation-mediated toxicity resulting either from gain-of-function mutations in specific proteins (as in polyglutamine diseases including Huntington's Disease) or from defects in the proteolytic machinery (as in early-onset Parkinson's Disease). The molecular targets of these toxic proteins need to be determined. We are in the process of constructing genetic models of both types of disorders. The goal of these studies is to elucidate the molecular mechanisms underlying these disorders, and relay this understanding to the development of new therapeutics.