- Ph.D., Massachusetts Institute of Technology, 1983
- B.A., Princeton University, 1979
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.
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.
- Dynamic human MutSα-MutLα complexes compact mismatched DNA.
- 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.
- Proc Natl Acad Sci U S A (2020 Jul 14) 117:16302-16312. Abstract/Full Text
- In vitro studies of DNA mismatch repair proteins.
- Geng H, Du C, Chen S, Salerno V, Manfredi C, Hsieh P.
- Anal Biochem (2011 Jun 15) 413:179-84. Abstract/Full Text
Research in Plain Language
All organisms have to withstand threats to the integrity of their genome. For example, when DNA is replicated prior to cell division, errors can occur that if uncorrected, lead to mutation. Normally, these errors are relatively rare as replication involving large protein complexes is a high-fidelity process with a built-in proofreading step. Nevertheless, newly replicated DNA can sometimes contain mispaired bases or small insertions or deletions of bases. A highly conserved DNA repair pathway, DNA mismatch repair, targets these mismatches, excises a region in the newly synthesized DNA strand containing the error and resynthesizes the DNA to restore the original genetic information. Individuals missing this repair pathway have increased susceptibility to cancer. We study the molecular mechanisms by which this repair occurs and the consequences to a cell when mismatch repair is missing or defective.