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Review
. 2009 Mar 12;364(1517):613-9.
doi: 10.1098/rstb.2008.0206.

Competitive repair pathways in immunoglobulin gene hypermutation

Claude-Agnès Reynaud  1 , Frédéric Delbos, Ahmad Faili, Quentin Guéranger, Said Aoufouchi, Jean-Claude Weill
Affiliations
Review

Competitive repair pathways in immunoglobulin gene hypermutation

Claude-Agnès Reynaud et al. Philos Trans R Soc Lond B Biol Sci. .

Abstract

This review focuses on the contribution of translesion DNA polymerases to immunoglobulin gene hypermutation, in particular on the roles of DNA polymerase eta (Poleta) in the generation of mutations at A/T bases from the initial cytosine-targeted activation-induced cytidine deaminase (AID)-mediated deamination event, and of Polkappa, an enzyme of the same polymerase family, used as a substitute when Poleta is absent. The proposition that the UNG uracil glycosylase and the MSH2-MSH6 mismatch recognition complex are two competitive rather than alternative pathways in the processing of uracils generated by AID is further discussed.

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Figures

Figure 1
Figure 1
Profound alteration of the mutation profile of MSH2-deficient B cells. (a) A two- to three-fold reduction in hypermutation in MSH2-deficient B cells. Mutation frequency of JH4 intronic sequences from Peyer's patch PNAhigh B cells was determined for individual mice. (b) A bias for G/C transitions in JH4 sequences from Peyer's patch B cells in MSH2-deficient animals. (c) A schematic of the distribution of mutations along the JH4 intronic sequence of Peyer's patch PNAhigh B cells, with G/C mutations plotted above the line representing the JH4 sequence and A/T mutations below. This conceptual representation illustrates the similar quantitative levels of G/C mutagenesis at hotspot positions between the Msh2×Ung−/− and the Msh2−/− backgrounds, while being greatly diminished at other G/C bases. G/C mutagenesis is overall lower in the wild-type context, in which approximately half of the deaminated cytosines are repaired to generate mutations at A/T bases. Mutation data taken from Rada et al. (2004) and Delbos et al. (2007).
Figure 2
Figure 2
Competitive repair pathways in hypermutation. See text for detailed comments.
See this image and copyright information in PMC

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