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.  DNA mismatch repair (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 mutations at microsatellite repeat sequences  (termed microsatellite instability, MSI).  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. In addition to correcting DNA mismatches, the MMR system mediates an apoptotic response to DNA damage and both of these functions are thought to be important for genome maintenance and tumor suppression.  We have generated gene targeted 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. These studies have also revealed that MMR proteins play essential roles in class switch recombination and somatic hypermutation during antibody maturation and the control of meiotic recombination in mammals. We are currently studying the functions of MMR in intestinal stem cells (ISCs) and cancer stem cells (CSCs) in preclinical mouse models and how loss of MMR in stem cells affects tumorigenesis and the response of tumors to novel anticancer treatments including immune therapeutic approaches. 

Milano CR, Holloway JK, Zhang Y, Jin B, Smith C, Bergmann A, Edelmann W* and Cohen PE. 2019.  Mutation of the ATPase Domain of MutS Homolog-5 (MSH5) Reveals a Requirement for a Functional MutSγ Complex for All Crossovers in Mammalian Meiosis. G3 (Bethesda). g3.400074.2019. doi: 10.1534/g3.119.400074. PMID: 30944090  (*corresponding author).

Loss of MMR and TGFBR2 increases the susceptibility to microbiota-dependent inflammation-associated colon cancer. Tosti E, Almeida AS, Tran TT, Barbachan e Silva M, Ó Broin P, Dubin R, Beck AP, Mclellan AS, Golden A, O’Toole PW and Edelmann W. 2022. Cell Mol Gastroenterol Hepatol. 2022 Jun 7:S2352-345X(22)00095-9. doi: 10.1016/j.jcmgh.2022.05.010. Online ahead of print. PMID: 35688320. 

Role of EXO1 nuclease activity in genome maintenance, the immune response and tumor suppression in Exo1^D173A mice. Wang S, Lee K, Gray S, Zhang Y, Tang C, Morrish RB, Pesenti E, Tosti E, van Oers J, Cohen PE, MacCarthy T, Roa S, Scharff M, Edelmann W* and Chahwan R. Nucleic Acid Research 2022 Jul 18:gkac616. doi: 10.1093/nar/gkac616. Online ahead of print. PMID: 35849338. (*corresponding author).

Vaccination and microbiota manipulation approaches for colon cancer prevention in rodent models. Tosti E, Srivastava N and Edelmann. Cancer Prev Res (Phila) 2023 April. CAPR-23-0015 PMID: 37012205.