My work is focused on understanding the role of Mre11 nuclease activities in resolving Topoisomerase I (Top1) lesions. Mre11 is an essential DNA repair molecule. Its activities include a 3'-5' double-stranded and single-stranded exonuclease, a DNA endonuclease, and an abasic lyase (Williams et al. 2007, Larson et al. 2005). In the presence of certain Top1-trapping poisons (i.e. camptothecin), Mre11 is essential for resolution of the covalent Top1-DNA complex and thus survival of the cell (Pommier 2006). I have identified mutations in Mre11 that increase sensitivity to camptothecin. I am using these alleles to elucidate the role of Mre11 in resolving Top1 lesions.
My primary model system is Saccharomyces cerevisiae. However, our findings have important implications for chemotherapeutic design, as camptothecin derivatives are used to treat Mre11-deficient colon cancers. Therefore I am also utilizing these mutants to illuminate the role of Mre11 in camptothecin sensitivity in the Mre11-deficient HCT116 colon carcinoma cell line. Resolving the question of how different alleles of Mre11 affect camptothecin sensitivity will not only answer questions about how TOP1 lesions are resolved, it will also further our understanding of the role of Mre11 polymorphisms in colorectal cancer and response to chemotherapy.
References:
Larson ED, Cummings WJ, Bednarski DW, Maizels N. Mol. Cell. (2005) 20:367-75.
Pommier. Nat. Rev. Cancer. (2006) 6:789-802.
Williams, R.S., Williams, J.S., Tainer, J.A. Biochem. Cell Biol. (2007) 85:509-520.
