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Review
, 14 (2), 235-40

Somatic Immunoglobulin Hypermutation

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Review

Somatic Immunoglobulin Hypermutation

Marilyn Diaz et al. Curr Opin Immunol.

Abstract

Immunoglobulin hypermutation provides the structural correlate for the affinity maturation of the antibody response. Characteristic modalities of this mechanism include a preponderance of point-mutations with prevalence of transitions over transversions, and the mutational hotspot RGYW sequence. Recent evidence suggests a mechanism whereby DNA-breaks induce error-prone DNA synthesis in immunoglobulin V(D)J regions by error-prone DNA polymerases. The nature of the targeting mechanism and the trans-factors effecting such breaks and their repair remain to be determined.

Figures

Figure 1
Figure 1
The emerging model of somatic hypermutation. (a) Specific elements in the intronic enhancer (iE) target hypermutation to the V(D)J region (the heavy-chain is used as an example; CH1 is its first constant region). A promoter (P) (although not necessarily the Ig promoter) is required for hypermutation. (b) The introduction of DNA-breaks in the V(D)J region leads to the opening of a gap. (c) Homologous recombination is initiated and uses the sister chromatid as a template. BCR cross-linking regulates the expression of translesion DNA polymerases, including ζ and η. This results in error-prone gap DNA synthesis, including mispair insertion (blue cross) by one of several translesion polymerases (blue sphere). (d) Mispair extension by polymerase ζ (yellow sphere) will then occur. (e) The resultant hypermutation allows for high-affinity antibodies to be produced.

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