Cited by 420DNA Repair MechanismsT-cell and B-cell ImmunologyRNA regulation and disease

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

Zeng, Xianmin, Winter, David B., Kasmer, Cynthia, Kraemer, Kenneth H., Lehmann, Alan R., Gearhart, Patricia J.·2001·Nature Immunology

DOI 10.1038/88740

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Abstract

To determine whether DNA polymerase eta 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 eta 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 eta 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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Wood, R. D., Gearhart, P. J. & Neuberger, M. S. Hypermutation in antibody genes. Phil. Trans. R. Soc. Lond. B 356, 1–125 (2001).

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Background
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Background
Adaptation to DNA damage and stimulation of genetic instability: the double-edged sword mammalian DNA polymerase κ
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The Role of Polymerase η in Somatic Hypermutation Determined by Analysis of Mutations in a Patient with Xeroderma Pigmentosum Variant
Yavuz, Ş., Yavuz, A. S., Kraemer, K. H., & Lipsky, P. E. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.7.3825 · Cited by 43
“response to AgR signaling in human tonsil B cells and in CL-01 Burkitt lymphoma cells (24), whereas it is up-regulated in murine germinal centers ( 18 ) and after stimulation of BL2 Burkitt lymphoma cells with T cells or IgM cross-linking (25).”
BackgroundResultInfluentialSelf-citation
Filling gaps in translesion DNA synthesis in human cells
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Activation-induced cytidine deaminase structure and functions: A species comparative view
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Altered Ig Hypermutation Pattern and Frequency in Complementary Mouse Models of DNA Polymerase ζ Activity
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“One such polymerase is DNA polymerase h, which has been shown to play a role in the misinsertion of bases at A:T sites during SHM (9, 10).”
BackgroundResult
Deletion of the Nucleotide Excision Repair Gene Ercc1 Reduces Immunoglobulin Class Switching and Alters Mutations Near Switch Recombination Junctions
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The absence of DNA polymerase κ does not affect somatic hypermutation of the mouse immunoglobulin heavy chain gene
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Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots
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High Mutability of the Tumor Suppressor Genes RASSF1 and RBSP3 (CTDSPL) in Cancer
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“It is reasonable to suggest that other(s) yet unknown DNA polymerase(s) may be responsible for the high mutability rates we report here and more than one polymerase contributes to hypermutations [29,31].”
Background
DNA polymerase η mutational signatures are found in a variety of different types of cancer
Rogozin, I. B., Goncearenco, A., Lada, A. G., De, S., Yurchenko, V., Nudelman, G., Panchenko, A. R., Cooper, D. N., & Pavlov, Y. I. (2018) · Cell Cycle · doi:10.1080/15384101.2017.1404208 · Cited by 39
Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation
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DNA Replication-Coupled PCNA Mono-Ubiquitination and Polymerase Switching in a Human In Vitro System
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A Backup Role of DNA Polymerase κ in Ig Gene Hypermutation Only Takes Place in the Complete Absence of DNA Polymerase η
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“The first experimental evidence for the implication of mutagenic polymerases in hypermutation came from the observation of Ig gene mutations in memory B cells from patients with the variant form of xeroderma pigmentosum (XPV) (5).”
BackgroundInfluential
A Role for the MutL Mismatch Repair Mlh3 Protein in Immunoglobulin Class Switch DNA Recombination and Somatic Hypermutation
Wu, X., Tsai, C. Y., Patam, M. B., Zan, H., Chen, J. P., Lipkin, S. M., & Casali, P. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.9.5426 · Cited by 37
“mlh3 / 15 (58) 11 (42) 12 (67) 6 (33) 11 (73) 4 (27) 16 (55) 13 (45) mlh3 / 10 (42) 14 (58) 5 (25) 15 (75) 11 (44) 14 (56) 4 (21) 15 (79)”
Rev1 is essential in generating G to C transversions downstream of the Ung2 pathway but not the Msh2+Ung2 hybrid pathway
Krijger, P. H. L., Tsaalbi‐Shtylik, A., Wit, N., van den Berk, P. C. M., de Wind, N., & Jacobs, H. (2013) · European Journal of Immunology · doi:10.1002/eji.201243191 · Cited by 36
Cis- and trans-factors affecting AID targeting and mutagenic outcomes in antibody diversification
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Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance
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The biochemistry of activation-induced deaminase and its physiological functions
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Normal hypermutation in antibody genes from congenic mice defective for DNA polymerase ι
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Self-citation
Antibody Diversification: Mutational Mechanisms and Oncogenesis
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In crystallo observation of three metal ion promoted DNA polymerase misincorporation
Chang, C., Luo, C. L., & Gao, Y. (2022) · Nature Communications · doi:10.1038/s41467-022-30005-3 · Cited by 35
Controlling somatic hypermutation in immunoglobulin variable and switch regions
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“For polymerase g, we first reported that it is an A:T mutator [ 33 ] after observing that the frequency of mutations of A and T dropped fourfold in V genes from patients with xeroderma pigmentosum disease, who lack polymerase g. This was confirmed in mice deficient in polymerase g [34, 35], where the frequency of A:T…”
BackgroundSelf-citation
Evaluation of Molecular Models for the Affinity Maturation of Antibodies: Roles of Cytosine Deamination by AID and DNA Repair
Samaranayake, M., Bujnicki, J. M., Carpenter, M. A., & Bhagwat, A. S. (2006) · Chemical Reviews · doi:10.1021/cr040496t · Cited by 35
Immunoglobulin diversification in DT40: a model for vertebrate DNA damage tolerance
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Novel aspects of macromolecular repair and relationship to human disease
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“Analysis of the Ig mutation pattern in B-cells from these patients reveals a marked decrease in mutations at A:T [114, 115], indicating that Pol h is involved in the MSH2 dependent pathway of SHM that generates mutations at A:T pairs.”
Background
Involvement of Rad18 in somatic hypermutation
Bachl, J., Ertongur, I., & Jungnickel, B. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605146103 · Cited by 34
Unravelling roles of error-prone DNA polymerases in shaping cancer genomes
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“Pol η mutable motifs are wellstudied because this polymerase performs translesion DNA synthesis and functions as the A/T mutator in vertebrate immunoglobulin genes (Ig) [116, 117].”
Background
Activation-induced cytidine deaminase (AID) is strongly expressed in the fetal bovine ileal Peyer's patch and spleen and is associated with expansion of the primary antibody repertoire in the absence of exogenous antigens
Liljavirta, J., Ekman, A., Knight, J. S., Pernthaner, A., Iivanainen, A., & Niku, M. (2013) · Mucosal Immunology · doi:10.1038/mi.2012.132 · Cited by 33
“The remainder can be attributed to selection, although other components of the mutation machinery may also contribute, such as the WA/TW mutator DNA polymerase Z recruited by AID-induced U:G mismatches.(17,30,35) The positive selection may be driven by unknown endogenous antigen(s).”
Background
Normal immunoglobulin gene somatic hypermutation in Polκ–Polι double-deficient mice
Shimizu, T., Azuma, T., Ishiguro, M., Kanjo, N., Yamada, S., & Ohmori, H. (2004) · Immunology Letters · doi:10.1016/j.imlet.2004.11.022 · Cited by 33
The role of activation-induced cytidine deaminase in antibody diversification, immunodeficiency, and B-cell malignancies
Luo, Z. K., Ronai, D., & Scharff, M. D. (2004) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2004.07.049 · Cited by 33

Authors: Zeng, X., Winter, D. B., Kasmer, C., Kraemer, K. H., Lehmann, A. R., & Gearhart, P. J.
Affiliations: National Institutes of Health (US)
Walter Reed Army Institute of Research (US)
University of Sussex (GB)
Corresponding author: Gearhart, Patricia J.
ORCID: Winter, David B.
Kraemer, Kenneth H.
Lehmann, Alan R.
Gearhart, Patricia J.
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2001-06
Volume: 2
Issue: 6
Pages: 537-541
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/88740
OpenAlex: W1560486125
Semantic Scholar: 8a9d17ca74ddcb4e43d0ff02f4b768b9cb457829
Cited by: 420
References: 49
Citations by year: 2026: 1 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 12 · 2019: 12 · 2018: 10 · 2017: 10 · 2016: 11 · 2015: 8 · 2014: 12 · 2013: 15 · 2012: 15
FWCI: 13.73
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Cancer Institute (Z01BC004517)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords: DNA polymerase eta, somatic hypermutation, immunoglobulin variable region genes, xeroderma pigmentosum variant, peripheral blood lymphocytes, error-prone mutagenesis
MeSH terms: Y-Family DNA Polymerases, Animals, B-Lymphocytes, Base Sequence, DNA, DNA-Directed DNA Polymerase, Genes, Immunoglobulin, Humans, Immunoglobulin Variable Region, Molecular Sequence Data, Mutation, Xeroderma Pigmentosum, Base Pairing, Mice

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

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