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

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Abstract
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 κ, 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 × 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 κ signature in Ig gene mutations of some XPV patients previously described, for whom residual Pol η activity might exist.