DNA MISMATCH REPAIR AND CANCER IN MURINE MODELS

Project: Research project

Project Details

Description

DESCRIPTION: The purpose of this study is to examine the role of the
mismatch repair proteins MSH3 and MSH6 in cancer susceptibility. Mutations
in the hMSH2 gene lead to HNPCC. Since MSH3 and MSH6 are thought to form
functional complexes with MSH2, the prediction is that knockout mice in
these genes will be cancer prone. Most of our understanding of the
properties of the mammalian DNA mismatch repair system is derived from
biochemical studies of the Escherichia coli MutHLS system. In bacteria the
repair of DNA mismatches, which are the result of DNA replication errors, is
initiated by the binding of the MutS protein to the mismatched bases. In
eukaryotes the recognition of DNA mismatches is more complex and requires
subsets of three different MutS homologs: MSH2, MSH3 and MSH6. Studies in
yeast have indicated the 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. Because germline mutations in hMSH2
lead to HNPCC it is likely that hMSH3 and hMSH6, which interact with hMSH2,
are also involved in the development of neoplasms. Their role in these
events, however, remains unclear. In this proposal we plan to test the
hypothesis that the mammalian homologs of yeast MSH3 and MSH6 share the same
function in mitotic mismatch repair and to analyze the cancer susceptibility
of mice carrying targeted mutations in these genes. The 3 specific aims of
this proposal are: 1. To generate mice that are deficient in MSH3 and MSH6
and to study the cancer susceptibility of these mouse lines. Dr. Edelmann
will study the consequences of loss of MSH3 and MSH6 for cancer
susceptibility with special emphasis on gastrointestinal carcinogenesis. 2.
To test the hypothesis that the mammalian msh2, msh3 and msh 6 genes are
genetically equivalent to their yeast homologs. Experiments in yeast
suggest the MSH2-MSH3 and MSH2-MSH6 are involved in the repair of different
types of DNA mismatches. We will use msh2, msh3 and msh6 mutant mouse lines
and double mutant msh3/msh6 mouse lines as a source for mouse embryonic
fibroblast cell lines to analyze microsatellite instability and to measure
heteroduplex mismatch repair in cell extracts. 3. To examine the effect of
MSH2, MSH3 and MSH6 deficiency of the Apc tumor suppressor gene. Colorectal
cancer cell lines with mutations in the hMSH2 gene accumulate mutations in
the tumor suppressor gene APC. We will generate mouse lines that are mutant
for msh3 or msh6 and heterozygous for the A1638 allele. The analysis of the
tumor spectrum and the onset and progression of tumor formation will
indicate the significance of MSH2, MSH3 and MSH6 for gastrointestinal
tumorigenesis and provide a detailed analysis of the spectrum of mutations
that results from deficiency in each of these repair genes.
StatusFinished
Effective start/end date12/1/9711/30/98

Funding

  • National Cancer Institute

ASJC

  • Genetics(clinical)
  • Genetics
  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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