Professor, Departments of Cell Biology
Professor, Department of Genetics
Price Bldg., Room 269/277
Genomic Instability and Cancer in Murine Models
The maintenance of genomic integrity in all organisms requires multiple DNA repair pathways that are involved in the processes of DNA replication, repair and recombination. Perturbations in these pathways can lead to increased mutation rates or chromosomal rearrangements that ultimately result in cancer. MMR is one of the repair systems that mammalian cells employ to maintain the integrity of its genetic information by correcting mutations that occur during erroneous replication. Mutations in MMR genes are linked to one of the most prevalent human cancer syndromes, Lynch syndrome and a significant number of sporadic colorectal cancers. At the molecular level tumors that develop in these patients display increased genomic mutation rates as indicated by increased instability at microsatellite repeat sequences (termed microsatellite instability, MIN).
MMR in eukaryotes is complex and involves several homologs of the bacterial MutS and MutL proteins. In mammals, the initiation of the repair process requires two complexes formed by three different MutS homologs (MSH):
- A complex between MSH2-MSH6 for the recognition of single base mismatches and
- A complex between MSH2-MSH3 for the recognition of insertion/deletions.
The repair reaction also requires a complex between the two MutL homologs MLH1 and PMS2 that interacts with the MSH complexes to activate subsequent repair events which include the excision of the mismatch carrying DNA strand and its re-synthesis. These steps are carried out by exonculeases, polymerases and a number of replication associated proteins. In addition to correcting DNA mismatches, the MMR system mediates an apoptotic response to DNA damage and suppresses recombination between non-identical sequences in mammalian genomes. All of these functions are thought to be important for genome maintenance and tumor suppression. We have generated knockout mouse lines with inactivating mutations in all the different MutS and MutL homologs, and also in genes that function in the later MMR steps to study their roles in genome maintenance and tumor suppression. In addition, we have generated knock-in mouse lines with missense mutations and conditional knockout mouse lines that inactivate specific MMR functions and/or model mutations found in humans.
Our studies indicate that specific MMR functions play distinct roles in maintaining genome stability and that defects in these functions have important consequences for tumorigenesis and the response of tumors to chemotherapeutic treatment. They have also revealed that some of the MMR proteins play essential roles in the control of meiotic recombination in mammals.