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Preferential cis–syn thymine dimer bypass by DNA polymerase η occurs with biased fidelity
Abstract
Human DNA polymerase eta (Pol eta) modulates susceptibility to skin cancer by promoting DNA synthesis past sunlight-induced cyclobutane pyrimidine dimers that escape nucleotide excision repair (NER). Here we have determined the efficiency and fidelity of dimer bypass. We show that Pol eta copies thymine dimers and the flanking bases with higher processivity than it copies undamaged DNA, and then switches to less processive synthesis. This ability of Pol eta to sense the dimer location as synthesis proceeds may facilitate polymerase switching before and after lesion bypass. Pol eta bypasses a dimer with low fidelity and with higher error rates at the 3' thymine than at the 5' thymine. A similar bias is seen with Sulfolobus solfataricus DNA polymerase 4, which forms a Watson-Crick base pair at the 3' thymine of a dimer but a Hoogsteen base pair at the 5' thymine (ref. 3). Ultraviolet-induced mutagenesis is also higher at the 3' base of dipyrimidine sequences. Thus, in normal people and particularly in individuals with NER-defective xeroderma pigmentosum who accumulate dimers, errors made by Pol eta during dimer bypass could contribute to mutagenesis and skin cancer.
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“This may have implications for the fidelity of lesion bypass, because both Dpo4 and human Pol have higher fidelity at the 5Ј T of a dimer than at the 3Ј T, and surprisingly, the fidelity of human Pol is slightly higher at the 5Ј T of a dimer than at the equivalent undamaged T (47).”
From DNA Replication Fidelity (2004) · cites this paper as [47]
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Metadata
- Authors
- McCulloch, S. D., Kokoska, R. J., Masutani, C., Iwai, S., Hanaoka, F., & Kunkel, T. A.
- Affiliations
- National Institutes of Health (US)
- The University of Osaka (JP)
- RIKEN (JP)
- Corresponding author
- Kunkel, Thomas A.
- Venue
- Nature
- Published
- 2004-03
- Volume
- 428
- Issue
- 6978
- Pages
- 97-100
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1581236180
- Cited by
- 246
- References
- 30
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 9 · 2017: 9 · 2016: 9 · 2015: 15 · 2014: 9 · 2013: 12 · 2012: 12
- FWCI
- 8.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust
- 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 › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- DNA polymerase eta, cyclobutane pyrimidine dimers, polymerase fidelity, polymerase processivity, nucleotide excision repair, xeroderma pigmentosum, UV mutagenesis, Hoogsteen base pairing, skin cancer predisposition
- MeSH terms
- Y-Family DNA Polymerases, DNA, DNA Damage, DNA-Directed DNA Polymerase, Humans, Hydrogen Bonding, Pyrimidine Dimers, Mutagenesis, Sulfolobus, Base Pairing
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