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DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes

Nature Immunology volume 2, pages 537–541 (2001)Cite this article

Abstract

To determine whether DNA polymerase η plays a role in the hypermutation of immunoglobulin variable genes, we examined the frequency and pattern of substitutions in variable VH6 genes from the peripheral blood lymphocytes of three patients with xeroderma pigmentosum variant disease, whose polymerase η had genetic defects. The frequency of mutation was normal but the types of base changes were different: there was a decrease in mutations at A and T and a concomitant rise in mutations at G and C. We propose that more than one polymerase contributes to hypermutation and that if one is absent, others compensate. The data indicate that polymerase η is involved in generating errors that occur predominantly at A and T and that another polymerase(s) may preferentially generate errors opposite G and C.

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Figure 1: Polymerase η is up-regulated in murine germinal center B cells.
Figure 2: Similar frequency of mutation in VH6-JH genes from XP-V and control subjects.
Figure 3: Similar location of independent mutations in the VH6 gene segment from XP-V and control clones.
Figure 4: Fewer A-T mutations in VH6-JH genes from XP-V patients compared to controls.

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Acknowledgements

We thank R. Tarone for statistical analyses, B. C. Broughton for the sequence analysis of the mutations in polymerase η in XP7BR and XP11BR, C. F. Arlett for the blood samples of XP7BR and XP11BR and F. Hanoaka for supplying intron information for murine polymerase η. We also thank R. Wood, K. Rosner and V. Bohr for critical comments and support.

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Authors and Affiliations

  1. Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, Baltimore, 21224, MD, USA

    Xianmin Zeng, Cynthia Kasmer & Patricia J. Gearhart

  2. Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, 20910, MD, USA

    David B. Winter

  3. Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Kenneth H. Kraemer

  4. MRC Cell Mutation Unit, University of Sussex, Brighton, UK

    Alan R. Lehmann

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  1. Xianmin Zeng
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Correspondence to Patricia J. Gearhart.

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Zeng, X., Winter, D., Kasmer, C. et al. DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol 2, 537–541 (2001). https://doi.org/10.1038/88740

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