Somatic mutation hotspots correlate with DNA polymerase η error spectrum

Rogozin, Igor B.; Pavlov, Youri I.; Bebenek, Katarzyna; Matsuda, Toshiro; Kunkel, Thomas A.

doi:10.1038/88732

Cited by 300DNA Repair MechanismsDNA and Nucleic Acid ChemistryRNA regulation and disease

Somatic mutation hotspots correlate with DNA polymerase η error spectrum

Rogozin, Igor B., Pavlov, Youri I., Bebenek, Katarzyna, Matsuda, Toshiro, Kunkel, Thomas A.·2001·Nature Immunology

DOI 10.1038/88732

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Abstract

Mutational spectra analysis of 15 immunoglobulin genes suggested that consensus motifs RGYW and WA were universal descriptors of somatic hypermutation. Highly mutable sites, "hotspots", that matched WA were preferentially found in one DNA strand and RGYW hotspots were found in both strands. Analysis of base-substitution hotspots in DNA polymerase error spectra showed that 33 of 36 hotspots in the human polymerase eta spectrum conformed to the WA consensus. This and four other characteristics of polymerase eta substitution specificity suggest that errors introduced by this enzyme during synthesis of the nontranscribed DNA strand in variable regions may contribute to strand-specific somatic hypermutagenesis of immunoglobulin genes at A-T base pairs.

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Signature 9 is a mutation pattern attributed to pol η recruited to repair AID-damaged DNA during somatic hypermutation in immunoglobulin genes.
“is characterized by a pattern of mutations that has been attributed to pol h (see the Discussion section for details) recruited for the repair of DNA damaged by AID during somatic hypermutation in immunoglobulin genes [28][29][30] .”
From DNA polymerase η mutational signatures are found in a variety of different types of cancer (2018) · cites this paper as [29]
pol η is unlikely to be involved in mutagenesis at undamaged DNA sites in normal skin cells.
“By contrast, there was no association between mutations and the WA/TW motif, associated with predominant errors of pol h when copying undamaged DNA 23,29 , indicating that pol h is unlikely to be involved in mutagenesis at undamaged DNA sites in normal skin cells (Table 1).”
From DNA polymerase η mutational signatures are found in a variety of different types of cancer (2018) · cites this paper as [29]
Signature 9 is characterized by a pattern widely attributed to pol η, although a higher frequency of T:A > G:C transversions compared to T:A > C:G transitions has not been observed in pol η studies in vitro or in vivo.
“although a higher frequency of T:A > G:C transversions compared to T:A > C:G transitions, has not been observed in studies of pol h either in vitro or in vivo 27,29 .”
From DNA polymerase η mutational signatures are found in a variety of different types of cancer (2018) · cites this paper as [29]
Some endogenous or exogenous mutational mechanisms may have very similar or identical signatures, so a given signature cannot be attributed solely and exclusively to one molecular mechanism.
“In fact, we can never be sure that a given mutational signature can be attributed solely and exclusively to one molecular mechanismindeed, some endogenous or exogenous mutational mechanisms may have very similar or even identical signatures 27,29 .”
From DNA polymerase η mutational signatures are found in a variety of different types of cancer (2018) · cites this paper as [29]

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Authors: Rogozin, I. B., Pavlov, Y. I., Bebenek, K., Matsuda, T., & Kunkel, T. A.
Affiliations: Russian Academy of Sciences (RU)
National Institutes of Health (US)
Corresponding author: Kunkel, Thomas A.
ORCID: Rogozin, Igor B.
Pavlov, Youri I.
Kunkel, Thomas A.
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2001-06
Volume: 2
Issue: 6
Pages: 530-536
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/88732
OpenAlex: W1580707139
Cited by: 298
References: 54
Citations by year: 2025: 4 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 10 · 2015: 5 · 2014: 13 · 2013: 12 · 2012: 11
FWCI: 9.56
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords: somatic hypermutation, DNA polymerase eta, mutational spectra, immunoglobulin genes, variable region, AT base pairs
MeSH terms: Y-Family DNA Polymerases, Amino Acid Sequence, Animals, Base Sequence, DNA, DNA-Directed DNA Polymerase, Genes, Immunoglobulin, Humans, Molecular Sequence Data, Mutation, Consensus Sequence, Base Pairing, Amino Acid Motifs, Mice

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Somatic mutation hotspots correlate with DNA polymerase η error spectrum

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