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Published 20 January 2004. doi:10.1084/jem.20031831
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 2, 265-270
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DNA Polymerase {eta} Is Involved in Hypermutation Occurring during Immunoglobulin Class Switch Recombination

Ahmad Faili1, Said Aoufouchi1, Sandra Weller1, Françoise Vuillier2, Anne Stary3, Alain Sarasin3, Claude-Agnès Reynaud1, and Jean-Claude Weill1

1 INSERM U373, Faculté de Médecine Necker-Enfants Malades, Université Paris V, 75730 Paris, France
2 Unité d'Immuno-Hématologie et d'Immunopathologie, Institut Pasteur, 75724 Paris, France
3 Etude des Relations Instabilité Génétique et Cancer, CNRS UPR 2169, Institut Gustave Roussy, 94805 Villejuif, France

Address correspondence to Jean-Claude Weill, INSERM U373, Faculté de Médecine Necker-Enfants Malades, Université Paris V, 156 Rue de Vaugirard, 75730 Paris, France. Phone: 33-1-40-61-53-80; Fax: 33-1-40-61-55-90; email: weill{at}necker.fr; or Claude-Agnès Reynaud, INSERM U373, Faculté de Médecine Necker-Enfants Malades, Université Paris V, 156 Rue de Vaugirard, 75730 Paris, France. Phone: 33-1-40-61-56-84; Fax: 33-1-40-61-55-90; email: reynaud{at}necker.fr

Base substitutions, deletions, and duplications are observed at the immunoglobulin locus in DNA sequences involved in class switch recombination (CSR). These mutations are dependent upon activation-induced cytidine deaminase (AID) and present all the characteristics of the ones observed during V gene somatic hypermutation, implying that they could be generated by the same mutational complex. It has been proposed, based on the V gene mutation pattern of patients with the cancer-prone xeroderma pigmentosum variant (XP-V) syndrome who are deficient in DNA polymerase {eta} (pol {eta}), that this enzyme could be responsible for a large part of the mutations occurring on A/T bases. Here we show, by analyzing switched memory B cells from two XP-V patients, that pol {eta} is also an A/T mutator during CSR, in both the switch region of tandem repeats as well as upstream of it, thus suggesting that the same error-prone translesional polymerases are involved, together with AID, in both processes.

Key Words: somatic mutation • pol {eta} • translesional DNA polymerases • xeroderma pigmentosum variant syndrome

C.-A. Reynaud and J.-C. Weill are senior authors on this paper.

Abbreviations used in this paper: AID, activation-induced cytidine deaminase; CSR, class switch recombination; pol {eta}, polymerase {eta}; TLS, translesion DNA synthesis; S{alpha}, {alpha} switch region; SHM, somatic hypermutation; Sµ, µ switch region; XP-V, xeroderma pigmentosum variant.


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