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

¹ Radiation Oncology Research Laboratory, Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201
² Section on DNA Replication, Repair and Mutagenesis, Laboratory of Genomic Integrity, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD 20892
³ Laboratory of Molecular Gerontology, National Institute on Aging, Bethesda, MD 20892
⁴ Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
⁵ Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
⁶ Discovery Research Institute, RIKEN and Core Research for Evolutional Sciences and Technology, Japan Science and Technology Corporation, Saitama 351-0198, Japan

CORRESPONDENCE Patricia J. Gearhart: gearhartp{at}grc.nia.nih.gov

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

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Identifying protein–protein interactions in somatic hypermutation

Myron F. Goodman and Matthew D. Scharff
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