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. In a process that is poorly understood, the signaling kinase ATR mediates cell killing in response to O6-meG, but only in the presence of the MMR proteins MutSα and MutLα. Thus, inactivation of MMR renders tumor cells resistant to killing by alkylating drugs, a class of chemotherapeutic agents widely used in cancer treatment. 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.
Applying our Research
The loss of mismatch repair is the leading cause of a genetic predisposition to colorectal cancer, and the loss of other repair pathways and key components of DNA damage signaling pathways are also associated with cancer. Understanding at a basic level how genome instability contributes to cancer and how repair and signaling pathways blunt this risk is critical to the eventual development of new therapeutic approaches.
Need for Further Study
DNA repair and damage signaling are interconnected processes and utilize a complicated cascade of molecular interactions involving key protein-DNA complexes that signal, license, and regulate cellular responses. Defining these key molecular interactions using a variety of approaches—genetic, biochemical, structural, cell biological and biophysical—is an ongoing goal.