A backup role of DNA polymerase κ in Ig gene hypermutation only takes place in the complete absence of DNA polymerase η

Ahmad Faili, Anne Stary, Frédéric Delbos, Sandra Weller, Said Aoufouchi, Alain Sarasin, Jean Claude Weill, Claude Agnès Reynaud

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    Résumé

    Patients with the variant form of xeroderma pigmentosum (XPV) syndrome have a genetic deficiency in DNA polymerase (Pol) η, 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 η, is used as backup for Ig gene hypermutation in both humans and mice in cases of complete Pol η deficiency, a proposition supported in this study by the analysis of Pol η x Pol κ 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 η protein. Whereas the Pol η 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 η signature. Pol η 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 η signature in Ig gene mutations of some XPV patients previously described, for whom residual Pol η activity might exist.

    langue originaleAnglais
    Pages (de - à)6353-6359
    Nombre de pages7
    journalJournal of Immunology
    Volume182
    Numéro de publication10
    Les DOIs
    étatPublié - 15 mai 2009

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