Paul L. Modrich (Primary)

James B. Duke Professor of Biochemistry
Duke Cancer Institute Member
Modrich Lab, Primary Faculty
Research Interests: 

Nucleic Acid Biochemistry, Cancer Biology, Origins of Mutation

Lab Location
Nanaline Duke Room 156A
Office Location

Nanaline Duke Room 156A, Durham, NC 27710
Box 3711 Med Ctr, Durham, NC 27710

(919) 684-2775

We study mismatch repair, an important regulator of mutation production that corrects DNA biosynthetic errors, suppresses recombination between quasi-homologous DNA sequences, and in mammalian cells, participates in the cellular response to certain types of DNA chemical damage. Inactivation of human mismatch repair confers strong cancer predisposition and renders tumor cells resistant to certain chemotherapeutic drugs.  As one approach to understanding this pathway, we have identified the activities responsible for replication error correction in both E. coli and human cells and have reconstituted strand-directed repair of mismatched base pairs using purified components in both cases.  Analysis of these reactions, as well as partial reactions supported by subsets of the required proteins, has clarified the mechanisms of E. coli and human mismatch repair.  In the case of the human pathway, these studies have established the functions of MutSalpha and MutLalpha, defects in either of which are the cause of Lynch syndrome, the most common form of hereditary cancer.

Current work addresses involvement of human mismatch repair in the cellular response to anti-cancer DNA-damaging drugs, inhibition of human mismatch repair by the carcinogen/mutagen Cd2+, and function of the pathway in the expansion of (CAG)n/(CTG)n triplet repeat sequences, the cause of a number of neurodegenerative diseases.

Honors and Awards
  • Nobel Prize in Chemistry 2015.  Royal Swedish Academy of Sciences
  • American Cancer Society Medal of Honor.  2005
  • Fellow, American Academy of Arts and Sciences.  2004
  • Member, Institute of Medicine.  2003
  • Feodor Lynen Medal.  2000
  • General Motors Mott Prize in Cancer Research.  1996
  • Member, National Academy of Sciences.  1993
Education

PhD Stanford University, 1973
BS Massachusetts Institute of Technology, 1968

Publications
  1. Shao, H, Baitinger, C, Soderblom, EJ, Burdett, V, and Modrich, P. "Hydrolytic function of Exo1 in mammalian mismatch repair." Nucleic Acids Research 42, no. 11 (June 17, 2014): 7104-7112.
  2. Pluciennik, A, Burdett, V, Baitinger, C, Iyer, RR, Shi, K, and Modrich, P. "Extrahelical (CAG)/(CTG) triplet repeat elements support proliferating cell nuclear antigen loading and MutLalpha endonuclease activation." Proceedings of the National Academy of Sciences of the United States of America 110, no. 30 (2013): 12277-12282.
  3. Liu, Y., Kadyrov, F. A., and Modrich, P. (2011) "PARP-1 enhances the mismatch-dependence of 5’-directed excision in human mismatch repair in vitro", DNA Repair 10, 1145-1153, PMCID: 3222275.
  4. Orans, J., McSweeney, E. A., Iyer, R. R., Hellinga, H. W., Modrich, P. and Beese, L. S. (2011) "Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family", Cell 145, 212-223, PMCID: 3093132.
  5. Pluciennik, A., Dzantiev, L., Iyer, R. R., Constantin, N., Kadyrov, F. A. and Modrich, P. (2010) "PCNA function in the activation and strand-direction of MutLalpha endonuclease in mismatch repair", Proc. Natl. Acad. Sci. U. S. A. 107, 16066-16071, PMCID: PMC2941292.