| First Author | Faili A | Year | 2009 |
| Journal | J Immunol | Volume | 182 |
| Issue | 10 | Pages | 6353-9 |
| PubMed ID | 19414788 | Mgi Jnum | J:150294 |
| Mgi Id | MGI:3850285 | Doi | 10.4049/jimmunol.0900177 |
| Citation | Faili A, et al. (2009) A backup role of DNA polymerase kappa in Ig gene hypermutation only takes place in the complete absence of DNA polymerase eta. J Immunol 182(10):6353-9 |
| abstractText | Patients with the variant form of xeroderma pigmentosum (XPV) syndrome have a genetic deficiency in DNA polymerase (Pol) eta, 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 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 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 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. |
