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

作者：Faili Ahmad; Stary Anne; Delbos Frederic; Weller Sandra; Aoufouchi Said; Sarasin Alain; Weill Jean Claude; Reynaud Claude Agnes^*

来源：The Journal of Immunology, 2009, 182(10): 6353-6359.

DOI：10.4049/jimmunol.0900177

Patients with the variant form of xeroderma pigmentosum (XPV) syndrome have a genetic deficiency in DNA polymerase (poll eta, and display accordingly an increased skin sensitivity to UV light, as well as all altered mutation pattern of their Ig V genes in memory R cells, alteration that consists in a reduced mutagenesis at A/T bases. We previously suggested that another polymerase with a different mutation signature, Pol kappa, is used as backup for Ig gene hypermutation in both humans and mice in cases of complete Pol eta deficiency, a proposition supported in this study by the analysis of Pol eta X Pol kappa 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 eta protein. Whereas the Pol eta 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 It cells. Memory B cells from this patient showed a 50% reduction in A/T mutations, with a spectrum that still displays a strict Pol eta signature. Pol eta 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 kappa signature in Ig gene mutations of some XPV patients previously described, for whom residual Pol eta activity might exist. The journal of Immunology, 2009, 182: 6353-6359.

• 出版日期2009-5-15