Paul L. Modrich

Duke University

Election Year: 1993
Primary Section: 21, Biochemistry
Membership Type: Member

Research Interests

We study mismatch correction, a DNA repair system that prevents mutations by rectifying 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 damage. We have reconstituted bacterial mismatch repair in a purified system and are studying the mechanism of this complex reaction. We have also identified several key activities required for human mismatch repair and have shown that biochemical defects in this system are associated with tumor formation in hereditary nonpolyposis colon cancer (Lynch syndrome), as well as a subset of sporadic cancers that occur in a variety of tissues. Defects in the human repair system also render tumor cells resistant to the cytotoxic effects of certain chemotherapeutic drugs, including DNA methylators, cisplatin and doxorubicin. We believe that recognition of certain classes of DNA damage by the mismatch repair system initiates a sequence of events that leads to cell death. Goals of current work include identification of other components of the human mismatch repair system and clarification of the mechanism by which recognition of DNA damage by the repair system triggers a cell death response.

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