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A Backup Role of DNA Polymerase in Ig Gene Hypermutation Only Takes Place in the Complete Absence of DNA Polymerase ¹

Ahmad Faili^2,*, Anne Stary^2,, Frédéric Delbos^*, Sandra Weller^*, Said Aoufouchi^*, Alain Sarasin, Jean-Claude Weill^* and Claude-Agnès Reynaud^3,*

^* Institut National de la Santé et de la Recherche Médicale Unite 783 "Développement du système immunitaire," Université Paris Descartes, Faculté de Médecine, Site Necker-Enfants Malades, Paris, France; and Centre National de la Recherche Scientifique FRE 2939 Stabilité génétique et oncogénèse, Université Paris Sud, Institut Gustave Roussy, Villejuif, France

Patients with the variant form of xeroderma pigmentosum (XPV) syndrome have a genetic deficiency in DNA polymerase (Pol) , and display accordingly an increased skin sensitivity to UV light, as well as an altered mutation pattern of their Ig V genes in memory B cells, alteration that consists in a reduced mutagenesis at A/T bases. We previously suggested that another polymerase with a different mutation signature, Pol , is used as backup for Ig gene hypermutation in both humans and mice in cases of complete Pol deficiency, a proposition supported in this study by the analysis of Pol x Pol double-deficient mice. We also describe a new XPV case, in which a splice site mutation of the first noncoding exon results in a decreased mRNA expression, a mRNA that otherwise encodes a normal Pol protein. Whereas the Pol mRNA level observed in patient’s fibroblasts is one-twentieth the value of healthy controls, it is only reduced to one-fourth of the normal level in activated B cells. Memory B cells from this patient showed a 50% reduction in A/T mutations, with a spectrum that still displays a strict Pol signature. Pol thus appears as a dominant enzyme in hypermutation, its presence precluding the use of a substitute enzyme even in conditions of reduced availability. Such a dominant behavior may explain the lack of Pol signature in Ig gene mutations of some XPV patients previously described, for whom residual Pol activity might exist.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Ligue Nationale contre le Cancer (Equipe labellisée), the Fondation Princesse Grace de Monaco (to J.-C.W.), and the Ministry of Health (to A.S.).

² A.F. and A.S. share equal contribution.

³ Address correspondence and reprint requests to Claude-Agnès Reynaud or Jean-Claude Weill, Institut National de la Santé et de la Recherche Médicale Unite 783, 156 rue de Vaugirard, Paris Cedex 15, France 75730; E-mail address: claude-agnes.reynaud{at}inserm.fr or jean-claude.weill{at}inserm.fr

⁴ Abbreviations used in this paper: AID, activation-induced cytidine deaminase; β₂m, β₂-microglobulin; PNA, peanut lectin; Pol, DNA polymerase; UNG, uracil glycosylase; XPV, variant form of xeroderma pigmentosum; MSH, MutS homolog.

⁵ The online version of this article contains supplemental material.