Manju Hingorani, professor of molecular biology and biochemistry, was awarded a grant of $408,609 from the National Institutes of Health (NIH) to study the structure and mechanisms of DNA repair proteins responsible for fixing errors in the genetic code and preventing carcinogenesis.
The three-year grant will fund PhD and undergraduate students’ research on DNA mismatch repair (MMR). MMR corrects base mismatches and loops in DNA, and is therefore a critical guardian of genetic and cellular integrity. Defects in this essential, evolutionarily conserved DNA repair process cause high levels of mutations in the genome, which in turn lead to cancer. In humans, MMR defects manifest most frequently in a hereditary disorder known as Lynch Syndrome (LS), which substantially raises the risk of colorectal, endometrial and many other cancers.
A large number of MMR defects occur due to small, single-amino-acid changes in the MutS protein that initiates the repair reaction. Hinagorani’s research group has been investigating MMR proteins for the past 15 years. The group now has a detailed enough understanding of the MutS biochemical mechanism to determine how changing single amino acids affects MutS structure and function enough to disrupt MMR. In addition to experimental research, the project also builds on computational modeling done in collaboration with Joshua Boger University Professor of the Sciences and Mathematics David Beveridge’s group in the Chemistry Department, and Professor Saraswathi Vishveshwara’s group at the the Indian Institute of Science in Bangalore, India. Beverage is also professor of chemistry. The researchers hope that by applying biochemical, biophysical and computational approaches in an interdisciplinary manner, students will gain new knowledge about MutS function and, thereby, a better understanding of the basis for its malfunction in cancer.