TY - JOUR
T1 - A backup role of DNA polymerase κ in Ig gene hypermutation only takes place in the complete absence of DNA polymerase η
AU - Faili, Ahmad
AU - Stary, Anne
AU - Delbos, Frédéric
AU - Weller, Sandra
AU - Aoufouchi, Said
AU - Sarasin, Alain
AU - Weill, Jean Claude
AU - Reynaud, Claude Agnès
PY - 2009/5/15
Y1 - 2009/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=76149097802&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.0900177
DO - 10.4049/jimmunol.0900177
M3 - Article
C2 - 19414788
AN - SCOPUS:76149097802
SN - 0022-1767
VL - 182
SP - 6353
EP - 6359
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -