Refining the Neuberger model: Uracil processing by activated B cells

Abstract

During the immune response, B cells undergo a programed mutagenic cascade to promote increased affinity and expanded antibody function. The two processes, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by the protein activation-induced deaminase (AID), which converts cytosine to uracil in the immunoglobulin loci. The presence of uracil in DNA promotes DNA mutagenesis though a subset of DNA repair proteins. Two distinct mechanisms have been proposed to control uracil processing. The first is through base removal by uracil DNA glycosylase (UNG), and the second is through detection by the mismatch repair (MMR) complex MSH2/6. In a study published in this issue of European Journal of Immunology, Dingler et al. [Eur. J. Immunol. 2014. 44: 1925-1935] examine uracil processing in B cells in the absence of UNG and SMUG1 glycosylases. Similar to UNG, SMUG1 is an uracil glycosylase which can remove the uracil base. While Smug1(-/-) mice show no clear deficiency in SHM or CSR, Ung(-/-) Smug1(-/-) mice display exacerbated phenotypes, suggesting a back-up role for SMUG1 in antibody diversity. This new information expands the model of uracil processing in B cells and raises several interesting questions about the dynamic relationship between base excision repair and MMR.

Keywords: Class switch recombination; DNA repair; SMUG1; Somatic hypermutation; UNG.

Figure 1. The Neuberger model

The known mechanisms of uracil processing for CSR (left) and SHM (right) in (A) wild type or (B) Ung^−/− mice are depicted. Arrow thickness represents the relative efficiency of the pathway. Blue nucleotides represent DNA lesion, (U – uracil, * - abasic site). Red nucleotides represent fixed mutations. Orange represents enzymes. 1×, creates one nick; 2×, creates two nicks, TS, transition; TV, transversion.