Overview

Paul Modrich, James B. Duke Professor of Biochemistry, was awarded the 2015 Nobel Prize for Chemistry along with Tomas Lindahl of the Francis Crick Institute and Clare Hall Laboratory in the UK, and Aziz Sancar of University of North Carolina, Chapel Hill, for mechanistic studies of DNA repair.

Mismatch repair is a mutation avoidance system that stabilizes the genome by correcting DNA biosynthetic errors, by blocking recombination between diverged DNA sequences, and in the case of human cells, by targeting for death cells that have suffered certain types of DNA chemical damage. We have reconstituted E. coli mismatch repair in a pure system comprised of ten activities, including the MutH, MutL, MutS, and MutU proteins. Current work on the bacterial pathway addresses the mechanism of this complex reaction and reagent applications of the repair proteins for physical manipulation of DNA sequences based on genetic differences. We have shown that mismatch repair in human cells occurs by a mechanism similar to that of the bacterial reaction and depends on heterodimeric complexes of homologs of E. coli MutS and MutL proteins. Genetic defects in human MutS and MutL homologs are the cause of hereditary nonpolyposis colon cancer, as well as a signficant fraction of sporadic tumors that occur in a variety of tissues. Genetic inactivation of the human MutS and MutL proteins also confers resistance to some chemotherapeutic agents that kill by inducing an apoptotic respose. We have shown that the cytotoxic DNA lesions produced by these drugs are recognized by the human mismatch repair system, and have concluded that this event is the initial step in the sequence of events that leads to cell death. The molecular nature of the human repair system and its role in the cellular response to DNA damage are currently under study in the lab.

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