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Somatic hypermutation at A·T pairs: polymerase error versus dUTP incorporation

Nature Reviews Immunology volume 5, pages 171–178 (2005)Cite this article

Abstract

Somatic hypermutation of immunoglobulin genes occurs at both C·G pairs and A·T pairs. Mutations at C·G pairs are created by activation-induced deaminase (AID)-catalysed deamination of C residues to U residues. Mutations at A·T pairs are probably produced during patch repair of the AID-generated U·G lesion, but they occur through an unknown mechanism. Here, we compare the popular suggestion of nucleotide mispairing through polymerase error with an alternative possibility, mutation through incorporation of dUTP (or another non-canonical nucleotide).

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Figure 1: The DNA-deamination mechanism of somatic hypermutation.
Figure 2: Possible schemes for phase 2 mutation, yielding substitutions at A·T pairs.
Figure 3: Spectra of nucleotide substitutions.
Figure 4: Pathway of dUTP synthesis and breakdown in eukaryotes.

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Authors and Affiliations

  1. the Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Michael S. Neuberger, Javier M. Di Noia, Rupert C. L. Beale, Gareth T. Williams, Zizhen Yang & Cristina Rada

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DATABASES

Entrez Gene

AID

DNA polymerase-ζ

DNA polymerase-η

DNA polymerase-ι

exonuclease-1

MSH2

MSH6

UNG

Glossary

ABASIC SITE

A site in DNA where a nucleotide base has been removed by cleavage of the glycosidic bond that links the nucleotide base to the deoxyribose-phosphate backbone.

BASE-EXCISION REPAIR

A repair pathway that recognizes and eliminates from DNA particular non-canonical bases (such as deaminated or oxidized bases), replacing them with an appropriate base templated on the opposite strand.

CLONAL-SELECTION THEORY

A theory to account for the specificity of the adaptive humoral immune response, in which unknown processes were assumed to mediate the generation of diverse precursor cells, thereby resulting in the production of antibodies of different specificities. Antigen-mediated selection would then trigger clonal expansion and antibody secretion by those cells that produce a cognate antibody.

LESION-BYPASS DNA POLYMERASE

A DNA polymerase that can synthesize past a lesion (such as an abasic site or a base adduct) in the template strand.

LOW-FIDELITY DNA POLYMERASES

DNA polymerases that have a considerably higher rate of nucleotide misincorporation than the DNA polymerases that carry out normal chromosomal replication of the genome of the cell, so they frequently generate mismatched base pairs.

MISMATCH REPAIR

A repair pathway that recognizes and corrects mismatched base pairs, typically those that arise from errors of chromosomal DNA replication.

PATCH REPAIR

Repair of a DNA lesion by degrading a short patch of DNA on the damaged strand and resynthesizing it using the other strand as a template. The repair usually occurs at a time distinct from that at which the genome is replicated.

S PHASE

(Synthesis phase). The phase of the cell cycle during which the genomic DNA is replicated.

TRANSITION MUTATIONS

Base changes in DNA in which a pyrimidine (C or T) is replaced by another pyrimidine, or a purine (A or G) is replaced by another purine.

TRANSVERSION MUTATIONS

Base changes in DNA in which a pyrimidine (C or T) is replaced by a purine (A or G), or a purine is replaced by a pyrimidine.

WATSON–CRICK BASE PAIRING

The complementary alignment of purine (A or G) and pyrimidine (C, T or U) nucleotides on opposite nucleic-acid strands in pairings (C with G, and A with T or U) that allow maintenance of the double-helical conformation that was proposed by Watson and Crick.

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Neuberger, M., Noia, J., Beale, R. et al. Somatic hypermutation at A·T pairs: polymerase error versus dUTP incorporation. Nat Rev Immunol 5, 171–178 (2005). https://doi.org/10.1038/nri1553

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