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The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression
1Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
Repair of mismatches in DNA in mammalian cells is mediated by a complex of proteins that are members of two highly conserved families of genes referred to as MutS and MutL homologues. Germline mutations in several members of these families, MSH2, MSH6, MLH1, and PMS2, but not MSH3, are responsible for hereditary non-polyposis colorectal cancer. To examine the role of MSH3, we generated a mouse with a null mutation in this gene. Cells from Msh3-/- mice are defective in repair of insertion/ deletion mismatches but can repair base-base mismatches. Msh3-/- mice develop tumors at a late age. When the Msh3-/- and Msh6-/- mutations are combined, the tumor predisposition phenotype is indistinguishable from Msh2-/- or Mlh1-/- mice. These results suggest that MSH3 cooperates with MSH6 in tumor suppression.
Insights
The study found that MSH3 protein is crucial for repairing DNA insertion/deletion mismatches. Combining MSH3 and MSH6 gene mutations in mice led to tumor development, indicating MSH3
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- DNA mismatch repair (MMR) is vital for maintaining genomic stability.
- Mutations in MMR genes like MSH2, MSH6, MLH1, and PMS2 are linked to hereditary non-polyposis colorectal cancer (HNPCC).
- The specific role of MSH3 in MMR and cancer predisposition remained unclear.
Purpose of the Study:
- To investigate the function of the MSH3 gene in DNA mismatch repair.
- To determine the role of MSH3 in tumor suppression.
- To elucidate the relationship between MSH3 and other MMR genes in cancer development.
Main Methods:
- Generation of a mouse model with a null mutation in the MSH3 gene (Msh3-/-).
- Analysis of DNA mismatch repair capabilities in Msh3-/- cells.
- Assessment of tumor development in Msh3-/- mice and combined Msh3-/- and Msh6-/- mutant mice.
Main Results:
- Msh3-/- cells exhibited defects in repairing insertion/deletion mismatches but retained the ability to repair base-base mismatches.
- Msh3-/- mice developed tumors at a later age compared to wild-type mice.
- Combined Msh3-/- and Msh6-/- mutations resulted in a tumor predisposition phenotype identical to Msh2-/- or Mlh1-/- mice.
Conclusions:
- MSH3 plays a significant role in repairing insertion/deletion mismatches.
- MSH3 acts as a tumor suppressor.
- MSH3 cooperates with MSH6 in a critical pathway for tumor suppression, highlighting its importance in preventing cancer.