Winfried Edelmann, Ph.D

Professor, Department of Cell Biology Chanin Bldg., Room 602 718 430-2029 edelmann@aecom.yu.edu Biosketch Complete list of publications

Research interests Genetic Analysis of the Mammalian DNA Mismatch Repair System Our laboratory is studying the mammalian DNA Mismatch Repair (MMR) system using mouse lines with targeted mutations in the MMR genes. MMR is one of the repair systems that the cell employs to maintain the integrity of its genetic information. Mutations in members of the MMR gene family are linked to the human cancer syndrome hereditary nonpolyposis colorectal cancer (HNPCC). The mismatch repair system in eukaryotes is complex and involves several homologs of the bacterial MutS and MutL proteins. In mammals the initiation of the repair process is thought to require subsets of at least three different MutS homologs (MSH): MSH2, MSH3 and MSH6. Studies in yeast have indicated that DNA mismatch repair is initiated by two different complexes: A complex between MSH2-MSH6 for the recognition of single base mismatches and a complex between MSH2-MSH3 for the recognition of two to four base pair insertion/deletions. The mismatch repair system also requires a complex between the two MutL homologs MLH1 and PMS2 (postmeiotic segregation) that interacts with MSH2 to activate subsequent repair events. In addition to correcting DNA mismatches, the MMR system also 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 tumor suprression. Because germline mutations in the human MSH2 and MLH1 homologs lead to HNPCC, it is of considerable interest to investigate the effect of mutations in the other MSH homologs on tumorigenesis. We have used gene targeting to generate mouse lines with inactivating mutations in all the different MutS homologs, Mlh1 and also in genes that function in the later MMR steps such as mismatch excision. In addition, we are generating and analyzing mouse lines with missense mutations resembling the genetic changes found in either HNPCC patients or polymorhisms found in the normal human population. We are studying these mouse lines for their susceptibility to cancer and are using cell lines and biochemical assays to study the underlying molecular mechanisms. These studies include the molecular analysis of DNA repair and recombination mechanisms and DNA damage-induced apoptosis. Results obtained from these studies indicate that the individual MSH genes are functionally distinct in these activities and also with respect to their ability to confer cancer susceptibility in mammalian cells. They have also revealed that two other MutS homologs, MSH4 and MSH5, together with MLH1 and PMS2 function in the control of mammalian meiosis. Studies to gain insight into the meiotic role of these genes are underway.

Recent publications Wong E., Yang K., Kuraguchi M., Werling U., Avdievich E., Fa K., Fazzari M., Jin B., Brown A.M.T., Lipkin M. and Edelmann W. 2002. Mbd4 inactivation increases C-T transition mutations and promotes gastrointestinal tumor formation. Proc. Natl. Acad. Sci. USA 99:14937-14942. Wei K., Kucherlapati R, and Edelmann W. 2002. Mouse models for human DNA mismatch repair gene defects. Trends in Mol. Medicine 8:346-353. Wei, K., Clark, B. A., Wong, E., Kane, M. Mazur, D., Parris, T., Kolas, N., Russell, R., Kunkel, T., Kolodner, R., Cohen, P. and Edelmann, W. 2003. Inactivation of Exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. Genes Dev. 17:603-614. Lin D.P., Wang Y., Scherer S.J., Clark A.B., Yang K., Avdievich E., Jin B., Werling U., Parris T., Kurihara N., Umar A., Kucherlapati R., Lipkin M., Kunkel T.A. and Edelmann W. 2004. An Msh2 Point Mutation Uncouples DNA Mismatch Repair and Apoptosis. Cancer Res. 64: 517-522. Yang G., Scherer S.J., Shell S., Yang K., Kim M., Lipkin M., Kucherlapati R., Kolodner R.D. and Edelmann W. 2004. Dominant effects of an Msh6 missense mutation on DNA repair and cancer susceptibility. Cancer Cell 6:139-50.

Winfried Edelmann: Research interests | Biosketch Faculty research at a glance Birshtein | Bouhassira | Edelmann | Fyodorov | Keogh | Kielian | Kitsis | Nathenson | Query Scharff | Schildkraut | Shafritz | Singer | Skoultchi | Stanley | Steidl |Warner | Ye   Home