Peggy Hsieh, Ph.D.

Senior Investigator

Genome Dynamics Section, Genetics and Biochemistry Branch

NIDDK

Building 5, Room 324
5 Memorial Dr
Bethesda, MD 20814

+1 301 496 0306

peggyh@niddk.nih.gov

Research Topics

Our goal is to understand, at a molecular level, how DNA repair functions to protect the genome from a variety of toxic insults.  We also want to understand the consequences for organisms when repair pathways are knocked out or function inappropriately.

Current Research

All organisms have evolved DNA repair pathways and DNA damage response mechanisms to protect the integrity of the genome. DNA mismatch repair (MMR) is a highly conserved DNA excision repair pathway that contributes about 100-to 1000-fold to the overall fidelity of DNA replication and targets base-base mismatches (e.g., G:T mispairs and insertion/deletion loops). These mismatches arise as a result of replication errors particularly common in regions of mono- and dinucleotide repeats, the formation of heteroduplex DNA during homologous recombination, and replication opposite certain types of DNA damage. Loss of MMR predisposes individuals to colorectal and other cancers and gives rise to a mutator phenotype in which the rate of spontaneous mutation jumps many fold. MMR is also involved in alkylation repair and oxidative DNA damage, the establishment of tolerance to DNA damaging drugs, and the induction of cell cycle checkpoints and apoptosis in response to DNA damage. We study the molecular mechanisms underlying the repair process and the role of MMR proteins in the DNA damage response using biochemical, structural, and cell biological approaches.

Biography

  • Ph.D., Massachusetts Institute of Technology, 1983
  • B.A., Princeton University, 1979

Selected Publications

  1. Bradford KC, Wilkins H, Hao P, Li ZM, Wang B, Burke D, Wu D, Smith AE, Spaller L, Du C, Gauer JW, Chan E, Hsieh P, Weninger KR, Erie DA. Dynamic human MutSα-MutLα complexes compact mismatched DNA. Proc Natl Acad Sci U S A. 2020;117(28):16302-16312.

  2. Geng H, Sakato M, DeRocco V, Yamane K, Du C, Erie DA, Hingorani M, Hsieh P. Biochemical analysis of the human mismatch repair proteins hMutSα MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D). J Biol Chem. 2012;287(13):9777-91.

  3. Geng H, Du C, Chen S, Salerno V, Manfredi C, Hsieh P. In vitro studies of DNA mismatch repair proteins. Anal Biochem. 2011;413(2):179-84.

  4. Diouf B, Cheng Q, Krynetskaia NF, Yang W, Cheok M, Pei D, Fan Y, Cheng C, Krynetskiy EY, Geng H, Chen S, Thierfelder WE, Mullighan CG, Downing JR, Hsieh P, Pui CH, Relling MV, Evans WE. Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells. Nat Med. 2011;17(10):1298-303.

  5. Liu A, Yoshioka K, Salerno V, Hsieh P. The mismatch repair-mediated cell cycle checkpoint response to fluorodeoxyuridine. J Cell Biochem. 2008;105(1):245-54.


This page was last updated on April 26th, 2021