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B cells

What comes first: DNA cleavage or UNG?

Nature Reviews Immunology volume 4, page 747 (2004)Cite this article

The most widely accepted model (see Further reading) proposes that AID deaminates cytosine residues to uracil residues in immunoglobulin-gene DNA; the uracil residues are then removed by the DNA base-excision repair enzyme uracil-DNA glycosylase (UNG), resulting in strand breaks. However, Honjo and colleagues have proposed an alternative model — on the basis of similarities between AID and the mRNA-editing enzyme APOBEC1 — in which AID deaminates an unknown mRNA such that it encodes a novel endonuclease that cleaves the DNA. By looking at the temporal relationship between DNA breaks and UNG activity, they now put forward further evidence in favour of the RNA-editing model.

In these experiments, phosphorylated histone H2AX (γ-H2AX), which forms next to double-stranded DNA breaks, was used as a marker for cleavage sites involved in CSR. When a mouse lymphoma cell line was stimulated to switch to IgA production, γ-H2AX accumulated at the IgH loci. Expression of the UNG inhibitor Ugi by these cells reduced the level of CSR to IgA but did not affect γ-H2AX accumulation. Because γ-H2AX focus formation at the IgH loci does not depend on UNG, but CSR is reduced in the absence of UNG, this indicates that UNG has a role in CSR downstream of DNA cleavage, which contradicts the DNA-deamination model. In support of this, there was no difference in the IgH mutation rate between cells expressing or not expressing Ugi; because mutation results from DNA cleavage during CSR, it seems likely that UNG is not required for DNA cleavage.

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References

ORIGINAL RESEARCH PAPERS

  1. Begum, N. A. et al. Uracil DNA glycosylase activity is dispensable for immunoglobulin class switch. Science 305, 1160–1163 (2004)

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  2. Begum, N. A. et al. De novo protein synthesis is required for activation-induced cytidine deaminase-dependent DNA cleavage in immunoglobulin class-switch recombination. Proc. Natl Acad. Sci. USA 101, 13003–13007 (2004).

    Article  CAS  Google Scholar 

FURTHER READING

  1. Chaudhuri, J. & Alt, F. W. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nature Rev. Immunol. 4, 541–552 (2004).

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Authors
  1. Kirsty Minton
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Minton, K. What comes first: DNA cleavage or UNG?. Nat Rev Immunol 4, 747 (2004). https://doi.org/10.1038/nri1465

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