Maintaining the integrity of the genome is essential for normal cell growth and development, yet genomic DNA is routinely damaged by cellular metabolic processes, environmental exposure or via chemotherapeutic intervention. Stability and fidelity of the genome is thus preserved by a diverse group of DNA damage recognition and repair systems. The research in my lab focuses on both base excision repair (BER), one of the mechanisms responsible for the repair of DNA base damage and the cell survival pathways that are induced by such damage. In this BER pathway, DNA glycosylases recognize and remove base damage to form an abasic lesion; AP endonuclease hydrolyzes the DNA at the abasic lesion to yield a strand break containing a 5'deoxyribose phosphate (5'dRP) group; DNA polymerase ß (and other DNA polymerases) participates in both the strand tailoring (5'dRP removal) and DNA synthesis steps of BER and DNA ligation is conducted by one of several DNA ligases. This DNA repair mechanism is further complicated by functional partnerships with many other DNA interacting proteins, including but not limited to PARP, p53, XRCC1, RPA and p21. Defects or deficiencies in any of the individual steps of this pathway may contribute to spontaneous or DNA damage induced cell death or genome instability/tumor formation.
Using various methods of gene expression and regulation in both cell and animal models (mouse knockout models, transgenic cell and mouse models, RNA interference etc), we focus on three related research areas:
i. How is the BER pathway activated and how does it function in vivo.
ii. What additional gene products have a functional interaction with the BER pathway.
iii. What are the cellular responses to DNA base damage and DNA repair intermediates.
These studies include investigating interactions between the BER pathway and other DNA repair pathways, coordination of BER and the DNA damage response network and DNA damage mediated changes in gene expression, protein modification, induction of cell death mechanisms, cell cycle regulation and genome instability/tumor formation.