Error rate and specificity of human and murine DNA polymerase η
Open accessAbstract
We describe here the error specificity of mammalian DNA polymerase eta (pol eta), an enzyme that performs translesion DNA synthesis and may participate in somatic hypermutation of immunoglobulin genes. Both mouse and human pol eta lack intrinsic proofreading exonuclease activity and both copy undamaged DNA inaccurately. Analysis of more than 1500 single-base substitutions by human pol eta indicates that error rates for all 12 mismatches are high and variable depending on the composition and symmetry of the mismatch and its location. pol eta also generates tandem base substitutions at an unprecedented rate, and kinetic analysis indicates that it extends a tandem double mismatch about as efficiently as other replicative enzymes extend single-base mismatches. This ability to use an aberrant primer terminus and the high rate of single and double-base substitutions support the idea that pol eta may forego strict shape complementarity in order to facilitate highly efficient lesion bypass. Relaxed discrimination is further indicated by pol eta infidelity for a wide variety of nucleotide deletion and addition errors. The nature and location of these errors suggest that some may be initiated by strand slippage, while others result from additional mechanisms.
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DNA polymerase η copies undamaged DNA with lower fidelity than most DNA-directed polymerases, with an average base-substitution error rate of 3.5 × 10−2.
“DNA pol h copies undamaged DNA with a lower fidelity than most DNA-directed polymerases with an average base-substitution error rate of 3.5 £ 10 ¡2 [22][23][24] .”
From DNA polymerase <b>η</b> mutational signatures are found in a variety of different types of cancer (2018) · cites this paper as [23]
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 <b>η</b> mutational signatures are found in a variety of different types of cancer (2018) · cites this paper as [23]
The mutable motif of pol η is the short WA/TW sequence, defined in somatic hypermutation and in vitro systems.
“The mutable motif of pol h, the short motif WA/TW (W = A or T) was delineated in the context of somatic hypermutations and in vitro systems 22,23 .”
From DNA polymerase <b>η</b> mutational signatures are found in a variety of different types of cancer (2018) · cites this paper as [23]
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References 43 · Cited by 170
- Authors
- Matsuda, T., Bebenek, K., Masutani, C., Rogozin, I. B., Hanaoka, F., & Kunkel, T. A.
- Affiliations
- National Institutes of Health (US)
- The University of Osaka (JP)
- RIKEN (JP)
- Corresponding author
- Kunkel, Thomas A
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2001-09
- Volume
- 312
- Issue
- 2
- Pages
- 335-346
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2047426110
- Cited by
- 170
- References
- 43
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 6 · 2013: 14 · 2012: 9
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- public-domain
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, public-domain)
- 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
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- DNA polymerase eta, translesion synthesis, error rate, lesion bypass, somatic hypermutation, immunoglobulin genes, exonuclease proofreading, strand slippage, mismatch discrimination
- MeSH terms
- Y-Family DNA Polymerases, Animals, Base Sequence, DNA Damage, DNA Mutational Analysis, DNA-Directed DNA Polymerase, DNA Replication, Genes, Immunoglobulin, Humans, Kinetics, Lac Operon, Molecular Sequence Data, Substrate Specificity, Templates, Genetic, Mutagenesis, Frameshift Mutation, Point Mutation, Sequence Deletion, Base Pair Mismatch, Mice
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