Center for Molecular Medicine

Molecular Biology and Biochemistry Graduate Program

Research Interests
Colorectal cancer is the third most common cancer in men and women and ranks behind only lung cancer in cancer deaths. My laboratory is interested in studying the molecular biology of colorectal cancer development. The most common familial syndrome predisposing patients to increased colorectal cancer risk is hereditary non-polyposis colon cancer (HNPCC). HNPCC stems from mutations in DNA mismatch repair (MMR) genes. Although many functional details have emerged regarding the MMR system, the ultimate question of why defects in MMR cause cancer remains. Faulty MMR results in an elevated mutation rate (mutator phenotype), which has been proposed to lead to an accumulation of oncogene and tumor suppressor mutations that ultimately cause cancer. More recent work has revealed that MMR proteins play an important role in cell cycle arrest and apoptosis in response to certain DNA damaging agents. Thus, MMR mutations may affect tumorigenesis through multiple mechanisms. Our laboratory is interested in understanding what functions of the MMR system are affected during tumorigenesis.

We are currently focusing on two MMR genes, hMSH2 and hMSH6 . Their protein products function together as heterodimers to recognize a DNA lesion and initiate the repair/signaling process. Mutations of both genes have been identified in HNPCC patients; a subset of which are missense mutations. We are utilizing these cancer-associated missense mutants as tools to understand which functions of the normal MMR system are affected during tumorigenesis. Our approach includes an examination their biochemical and biophysical properties, their cellular functions including their ability to perform DNA repair, apoptosis and cell cycle checkpoint signaling, and finally, their in vivo effects on disease development and progression utilizing transgenic mouse models.

We are also interested in understanding whether MMR defects can be observed in the earliest pre-neoplastic colorectal lesion termed the aberrant crypt foci. These grossly identified aberrant crypts may be early biomarkers for cancer development and we wish to understand what role loss of MMR function plays in their formation and progression.

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