| First Author | Rada C | Year | 2002 |
| Journal | Curr Biol | Volume | 12 |
| Issue | 20 | Pages | 1748-55 |
| PubMed ID | 12401169 | Mgi Jnum | J:79590 |
| Mgi Id | MGI:2388528 | Doi | 10.1016/s0960-9822(02)01215-0 |
| Citation | Rada C, et al. (2002) Immunoglobulin Isotype Switching Is Inhibited and Somatic Hypermutation Perturbed in UNG-Deficient Mice. Curr Biol 12(20):1748-55 |
| abstractText | BACKGROUND: We have previously proposed that deamination of cytosine to uracil at sites within the immunoglobulin loci by activation-induced deaminase (AID) triggers antibody diversification. The pattern of diversification (phase 1 or 2 hypermutation, gene conversion, or switch recombination) is viewed as depending on the mode of resolution of the dU/dG lesion. A major resolution mode involves excising the uracil, an activity that at least four different enzymes can accomplish in the mouse.RESULTS: Deficiency in UNG uracil-DNA glycosylase alone is sufficient to distort the pathway of hypermutation in mice. In ung(-/-) animals, mutations at dC/dG pairs are dramatically shifted toward transitions (95%), indicating that the generation of abasic sites (which can induce transversions) has been inhibited. The pattern of substitutions at dA/dT pairs is unaffected. Class-switch recombination is substantially, but not totally, inhibited.CONCLUSIONS: The results provide strong support for the DNA deamination model for antibody diversification with respect to class-switching as well as hypermutation and, in the context of this model, suggest that (i) UNG is the major mouse DNA glycosylase responsible for processing the programmed dU/dG lesions within the immunoglobulin locus; (ii) the second (dA/dT-biased) phase of mutation is probably triggered by recognition of the initiating dU/dG lesion; and (iii) switch recombination largely proceeds via formation of an abasic site, although (iv) an UNG-independent pathway of switch recombination exists, which could reflect action by another uracil-DNA glycosylase but might alternatively be explained by a distinct pathway of resolution, for example, one involving MSH2/MSH6 recognition of the dU/dG lesion. |
