TY - JOUR
T1 - DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse
AU - Delbos, Frédéric
AU - Aoufouchi, Said
AU - Faili, Ahmad
AU - Weill, Jean Claude
AU - Reynaud, Claude Agnès
PY - 2007/1/22
Y1 - 2007/1/22
N2 - Mutations at A/T bases within immunoglobulin genes have been shown to be generated by a repair pathway involving the DNA-binding moiety of the mismatch repair complex constituted by the MSH2-MSH6 proteins, together with DNA polymerase η (pol η). However, residual A/T mutagenesis is still observed upon inactivation in the mouse of each of these factors, suggesting that the panel of activities involved might be more complex. We reported previously (Delbos, F., A. De Smet, A. Faili, S. Aoufouchi, J.-C. Weill, and C.-A. Reynaud. 2005. J. Exp. Med. 201:1191-1196) that residual A/T mutagenesis in pol η-deficient mice was likely contributed by another enzyme not normally involved in hypermutation, DNA polymerase κ, which is mobilized in the absence of the normal polymerase partner. We report the complete absence of A/T mutations in MSH2-pol η double-deficient mice, thus indicating that the residual A/T mutagenesis in MSH2-deficient mice is contributed by pol η, now recruited by uracil N-glycosylase, the second DNA repair pathway involved in hypermutation. We propose that this particular recruitment of pol η corresponds to a profound modification of the function of uracil glycosylase in the absence of the mismatch repair complex, suggesting that MSH2-MSH6 actively prevent uracil glycosylase from error-free repair during hypermutation. pol η thus appears to be the sole contributor of A/T mutations in the normal physiological context. JEM
AB - Mutations at A/T bases within immunoglobulin genes have been shown to be generated by a repair pathway involving the DNA-binding moiety of the mismatch repair complex constituted by the MSH2-MSH6 proteins, together with DNA polymerase η (pol η). However, residual A/T mutagenesis is still observed upon inactivation in the mouse of each of these factors, suggesting that the panel of activities involved might be more complex. We reported previously (Delbos, F., A. De Smet, A. Faili, S. Aoufouchi, J.-C. Weill, and C.-A. Reynaud. 2005. J. Exp. Med. 201:1191-1196) that residual A/T mutagenesis in pol η-deficient mice was likely contributed by another enzyme not normally involved in hypermutation, DNA polymerase κ, which is mobilized in the absence of the normal polymerase partner. We report the complete absence of A/T mutations in MSH2-pol η double-deficient mice, thus indicating that the residual A/T mutagenesis in MSH2-deficient mice is contributed by pol η, now recruited by uracil N-glycosylase, the second DNA repair pathway involved in hypermutation. We propose that this particular recruitment of pol η corresponds to a profound modification of the function of uracil glycosylase in the absence of the mismatch repair complex, suggesting that MSH2-MSH6 actively prevent uracil glycosylase from error-free repair during hypermutation. pol η thus appears to be the sole contributor of A/T mutations in the normal physiological context. JEM
UR - http://www.scopus.com/inward/record.url?scp=33846404877&partnerID=8YFLogxK
U2 - 10.1084/jem.20062131
DO - 10.1084/jem.20062131
M3 - Article
C2 - 17190840
AN - SCOPUS:33846404877
SN - 0022-1007
VL - 204
SP - 17
EP - 23
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -