MSH2-MSH6 stimulates DNA polymerase η, suggesting a role for A:T mutations in antibody genes

Teresa M. Wilson, Alexandra Vaisman, Stella A. Martomo, Patsa Sullivan, Li Lan, Fumio Hanaoka, Akira Yasui, Roger Woodgate, Patricia J. Gearhart

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    143 Citations (Scopus)

    Abstract

    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) η, 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 η in solution, and endogenous MSH2 associates with the pol in cell extracts. Third, MSH2-MSH6 stimulates the catalytic activity of pol η in vitro. These observations suggest that the interaction between MSH2-MSH6 and DNA pol η stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs.

    Original languageEnglish
    Pages (from-to)637-645
    Number of pages9
    JournalJournal of Experimental Medicine
    Volume201
    Issue number4
    DOIs
    Publication statusPublished - 2005 Feb 21

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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  • Cite this

    Wilson, T. M., Vaisman, A., Martomo, S. A., Sullivan, P., Lan, L., Hanaoka, F., Yasui, A., Woodgate, R., & Gearhart, P. J. (2005). MSH2-MSH6 stimulates DNA polymerase η, suggesting a role for A:T mutations in antibody genes. Journal of Experimental Medicine, 201(4), 637-645. https://doi.org/10.1084/jem.20042066