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.
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22 January 2007
Brief Definitive Report|
December 26 2006
DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse
Frédéric Delbos,
Frédéric Delbos
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
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Said Aoufouchi,
Said Aoufouchi
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
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Ahmad Faili,
Ahmad Faili
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
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Jean-Claude Weill,
Jean-Claude Weill
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
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Claude-Agnès Reynaud
Claude-Agnès Reynaud
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
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Frédéric Delbos
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
Said Aoufouchi
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
Ahmad Faili
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
Jean-Claude Weill
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
Claude-Agnès Reynaud
1Institut National de la Santé et de la Recherche Médicale U783 (“Développement du système immunitaire”)
2Université Paris René Descartes, Faculté de Médecine René Descartes, Site Necker–Enfants Malades, 75730 Paris Cedex 15, France
CORRESPONDENCE C.-A. Reynaud: [email protected] OR J.-C. Weill: [email protected]
Received:
October 04 2006
Accepted:
December 04 2006
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2007
J Exp Med (2007) 204 (1): 17–23.
Article history
Received:
October 04 2006
Accepted:
December 04 2006
Connected Content
Citation
Frédéric Delbos, Said Aoufouchi, Ahmad Faili, Jean-Claude Weill, Claude-Agnès Reynaud; DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse . J Exp Med 22 January 2007; 204 (1): 17–23. doi: https://doi.org/10.1084/jem.20062131
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