MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations in antibody genes.
Activation-induced cytidine deaminase deaminates cytosine to uracil (dU) in DNA, which leads to mutations at C:G basepairs in immunoglobulin genes during somatic hypermutation. The mechanism that generates mutations at A:T basepairs, however, remains unclear. It appears to require the MSH2-MSH6 mismatch repair heterodimer and DNA polymerase (pol) eta, as mutations of A:T are decreased in mice and humans lacking these proteins. Here, we demonstrate that these proteins interact physically and functionally. First, we show that MSH2-MSH6 binds to a U:G mismatch but not to other DNA intermediates produced during base excision repair of dUs, including an abasic site and a deoxyribose phosphate group. Second, MSH2 binds to pol eta in solution, and endogenous MSH2 associates with the pol in cell extracts. Third, MSH2-MSH6 stimulates the catalytic activity of pol eta in vitro. These observations suggest that the interaction between MSH2-MSH6 and DNA pol eta stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs.
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Related Subject Headings
- Somatic Hypermutation, Immunoglobulin
- Proto-Oncogene Proteins
- Protein Binding
- MutS Homolog 2 Protein
- Immunology
- Humans
- Hela Cells
- HeLa Cells
- DNA-Directed DNA Polymerase
- DNA-Binding Proteins
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Somatic Hypermutation, Immunoglobulin
- Proto-Oncogene Proteins
- Protein Binding
- MutS Homolog 2 Protein
- Immunology
- Humans
- Hela Cells
- HeLa Cells
- DNA-Directed DNA Polymerase
- DNA-Binding Proteins