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Emerging links between hypermutation of antibody genes and DNA polymerases

Nature Reviews Immunology volume 1, pages 187–192 (2001)Cite this article

Key Points

  • Hypermutation of antibody variable genes is restricted to discrete regions of DNA and occurs in B lymphocytes located in germinal centres. The process generates nucleotide substitutions, which can change amino acids and give an antibody molecule higher affinity for binding antigen.

  • DNA strand breaks are found in a 2-kilobase region that includes the rearranged variable gene and flanking sequences. Point mutations are distributed in the same area, which suggests that strand breaks initiate hypermutation.

  • The high frequency of mutation, one per 100 bases, suggests that error-prone DNA polymerases are involved. Several enzymes are being considered.

  • DNA polymerase ζ is present in mutating B cells, and antisense suppression of polymerase ζ decreases the mutation frequency by a few-fold. Further analyses will be complicated because polymerase - ζ-deficient mouse embryos die during mid-gestation.

  • DNA polymerase η is deficient in humans with the variant form of the disorder xeroderma pigmentosum (XP-V). Variable genes from XP-V individuals have a normal frequency of hypermutation, but the spectrum is shifted towards more mutations of G and C compared with A and T. A role for polymerase η as an A–T mutator in hypermutation is consistent with the types of error it makes when copying DNA in vitro.

  • DNA polymerase ι copies undamaged DNA with a very low fidelity. When filling in at the end of a template, its fidelity decreases even further. This might be relevant to hypermutation in which mutations are associated with sites of strand breaks.

  • DNA polymerase μ is highly expressed in B and T cells located in germinal centres, and has been suggested to be involved in hypermutation.

  • No single polymerase has been found to be responsible for all hypermutation. Several polymerases might participate in a specialized pathway for repair of directed strand breaks and mutations might be introduced in the process.

Abstract

Substantial antibody variability is created when nucleotide substitutions are introduced into immunoglobulin variable genes by a controlled process of hypermutation. Evidence points to a mechanism involving DNA repair events at sites of targeted breaks. In vertebrate cells, there are many recently identified DNA polymerases that inaccurately copy templates. Some of these are candidates for enzymes that introduce base changes during hypermutation. Recent research has focused on possible roles for DNA polymerases ζ (POLZ), η (POLH), ι (POLI), and μ (POLM) in the process.

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Figure 1: Location of mutations correlates with positions of strand breaks.
Figure 2: Speculative model for hypermutation.

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Acknowledgements

We thank C. Reynaud, R. Woodgate and L. Blanco for preprints and for sharing unpublished data.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, 21224, Maryland, USA

    Patricia J. Gearhart

  2. University of Pittsburgh Cancer Institute, S867 Scaife Hall, 3550 Terrace Street, Box 100, Pittsburgh, 15261, Pennsylvania, USA

    Richard D. Wood

Authors
  1. Patricia J. Gearhart
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Corresponding author

Correspondence to Patricia J. Gearhart.

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DATABASES

The following terms in this article are linked online to: LocusLink

AID

BCL6

DNA-PKCS

pol α

pol β

pol δ

pol ɛ

pol η

pol ι

pol κ

pol λ

pol μ

pol θ

pol ζ

Rag1

Rev1

TRF4

XRCC2

XRCC3

OMIM

HIGM2

XP-V

FURTHER INFORMATION

Human DNA repair genes

Patricia Gearhart's lab

Richard Wood's lab

Glossary

COMPLEMENTARITY-DETERMINING REGIONS

Amino acids found in three areas of each of the heavy and light chains that physically contact antigen, that is, they are complementary to the antigen.

AID

Activation-induced cytidine deaminase. A potential RNA-editing enzyme that is necessary for hypermutation and class-switch recombination.

CLASS SWITCHING

DNA rearrangement of the VDJ gene from IgM to any of the IgG, IgA and IgE constant genes at the heavy-chain locus. Recombination occurs in repetitive sequences of DNA located upstream of each constant gene.

NUCLEOTIDE EXCISION REPAIR

A DNA-repair pathway that repairs helix-distorting, covalent adducts in DNA (such as ultraviolet light-induced pyrimidine dimers). Incisions are made on the damaged strand flanking a lesion to release the damage in an oligonucleotide that is 24–32 residues long. The gap is filled by DNA-repair synthesis.

MISMATCH REPAIR

Mismatches arising in DNA because of errors made by replicative DNA polymerases are repaired by an excision system that removes a tract of DNA including the mismatch, and re-copies the original strand.

BASE EXCISION REPAIR

A DNA-repair pathway that removes single bases from DNA, such as uracil residues arising by deamination of cytosine. Repair is initiated by a DNA glycosylase enzyme that is specialized for a particular class of damage.

DNA CROSSLINKS

Covalent linkage of the two double-helical strands of DNA. Interstrand crosslinks can be caused by radiation and by chemicals, such as nitrogen mustards, photoactivated psoralens and mitomycin C.

XERODERMA PIGMENTOSUM

(XP). A rare inherited human disorder, in which patients display great sensitivity to the DNA-damaging effects of sunlight. XP can be caused by disabling any of eight different genes. The genes, denoted XPA–XPG, encode components of the nucleotide excision-repair pathway. The XPV gene encodes DNA polymerase η.

HOMOLOGOUS RECOMBINATION

Genetic recombination that occurs between DNAs with long stretches of homology. Double-strand breaks can be repaired if a chromosome or chromatid homologous with the broken DNA is available in the cell.

NON-HOMOLOGOUS END-JOINING

A pathway that rejoins DNA strand breaks without relying on significant homology. The main known pathway uses the Ku-end binding complex and is regulated by DNA protein kinase. The pathway is often used in mammalian cells to repair strand breaks caused by DNA-damaging agents, and some of the same enzymes are used during the strand-joining steps of V(D)J recombination.

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Gearhart, P., Wood, R. Emerging links between hypermutation of antibody genes and DNA polymerases. Nat Rev Immunol 1, 187–192 (2001). https://doi.org/10.1038/35105009

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