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Paul L. Modrich

James B. Duke Distinguished Professor Emeritus of Biochemistry
Biochemistry
Box 3711 Med Ctr, Durham, NC 27710
156A Nanaline H Duke, Durham, NC 27708

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.

Current Appointments & Affiliations


James B. Duke Distinguished Professor Emeritus of Biochemistry · 2022 - Present Biochemistry, Basic Science Departments
Professor Emeritus of Biochemistry · 2022 - Present Biochemistry, Basic Science Departments
Professor of Chemistry · 2015 - Present Chemistry, Trinity College of Arts & Sciences

In the News


Published November 10, 2021
As He Shuts Down His Lab, Nobel Prize Laureate Paul Modrich Looks Back at a Storied Career
Published November 5, 2021
One month before shutting down his lab, Paul Modrich looks back to his pathway to Nobel
Published October 5, 2018
Reflected Glory: 2018 Nobel Laureate Completed Early Award-Winning Study at Duke

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Recent Publications


Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion.

Journal Article Proc Natl Acad Sci U S A · February 18, 2020 MutL proteins are ubiquitous and play important roles in DNA metabolism. MutLγ (MLH1-MLH3 heterodimer) is a poorly understood member of the eukaryotic family of MutL proteins that has been implicated in triplet repeat expansion, but its action in this dele ... Full text Link to item Cite

The mutagen and carcinogen cadmium is a high-affinity inhibitor of the zinc-dependent MutLα endonuclease.

Journal Article Proc Natl Acad Sci U S A · July 10, 2018 MutLα (MLH1-PMS2 heterodimer), which acts as a strand-directed endonuclease during the initiation of eukaryotic mismatch repair, has been postulated to function as a zinc-dependent enzyme [Kosinski J, Plotz G, Guarné A, Bujnicki JM, Friedhoff P (2008) J Mo ... Full text Link to item Cite
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Recent Grants


Enzymology Of Eukaryotic Mismatch Repair

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 1991 - 2019

Forces and Long-Distance Coupling along DNA in the Mismatch Repair (MMR) Pathway

FellowshipMentor · Awarded by National Institutes of Health · 2014 - 2016

Clinical Oncology Research Career Development Program

ResearchMentor · Awarded by National Institutes of Health · 2009 - 2015

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Education, Training & Certifications


Stanford University · 1973 Ph.D.
Massachusetts Institute of Technology · 1968 B.S.