The Laboratory, headed by Dr. Richard D. Kolodner, is focused on three general areas:

1. The use of the yeast Saccharomyces cerevisiae as a model organism for identification of genes that function to suppress the accumulation of mutations and other types of genome rearrangements in DNA

2. The development of mice containing mutations in genes that suppress the accumulation of mutations and other types of genome rearrangements in DNA and the analysis of the role of these genes in suppressing cancer susceptibility

3. Gaining an understanding of the role of defects in these genes in inherited and sporadic cancers in humans.

Genetic studies have led to the demonstration that germline mutations in human genes encoding the major DNA mismatch repair system cause an inherited cancer susceptibility syndrome (HNPCC). In addition, some sporadic cancers develop defects in the mismatch repair gene MLH1 at an early step in tumorigenesis. Using the S. cerevisiae model system, two different advances have been made: for the first time, a biochemical role for proliferating cell nuclear antigen (PCNA) in mismatch repair has been elucidated by demonstrating that PCNA binds to the MSH2-MSH6 mismatch recognition complex and then transfers it to the mispaired base; and a model system for investigating polygenic interactions between mismatch repair defects has been developed and used to show that some human HNPCC causing mutations are actually weak mutations that interact genetically with other weak mutations to cause polygenic loss-of-function defects.

Through the generation of mutant mice combined with studies in which inherited mutations in the human MSH6 gene have been modeled in S. cerevisiae, it has been possible to identify separation-of-function mutations that inactivate mismatch repair but do not cause defects in the mismatch repair protein dependent DNA damage response. These mutations cause significantly increased cancer susceptibility demonstrating for the first time that increased mutation rates due to mismatch repair defects are sufficient to cause the development of cancer. In addition, the laboratory has developed a novel mutator assay in the yeast S. cerevisiae that allows detection of genome rearrangements like those seen in cancer cells. Using this assay, a number of genes were identified that function to prevent genome rearrangements.

Cancer Genetics