TY - JOUR
T1 - MSH2-MSH6 stimulates DNA polymerase η, suggesting a role for A:T mutations in antibody genes
AU - Wilson, Teresa M.
AU - Vaisman, Alexandra
AU - Martomo, Stella A.
AU - Sullivan, Patsa
AU - Lan, Li
AU - Hanaoka, Fumio
AU - Yasui, Akira
AU - Woodgate, Roger
AU - Gearhart, Patricia J.
PY - 2005/2/21
Y1 - 2005/2/21
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20042066
DO - 10.1084/jem.20042066
M3 - Article
C2 - 15710654
AN - SCOPUS:14244250387
SN - 0022-1007
VL - 201
SP - 637
EP - 645
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -