The Base Substitution Fidelity of DNA Polymerase β-dependent Single Nucleotide Base Excision Repair
Open accessAbstract
Damaged DNA bases are removed from mammalian genomes by base excision repair (BER). Single nucleotide BER requires several enzymatic activities, including DNA polymerase and 5′,2′-deoxyribose-5-phosphate lyase. Both activities are intrinsic to four human DNA polymerases whose base substitution error rate during gap-filling DNA synthesis varies by more than 10,000-fold. This suggests that BER fidelity could vary over a wide range in an enzyme dependent manner. To investigate this possibility, here we describe an assay to measure the fidelity of BER reactions reconstituted with purified enzymes. When human uracil DNA glycosylase, AP endonuclease, DNA polymerase β, and DNA ligase 1 replace uracil opposite template A or G, base substitution error rates are ≤0.3 to ≤2.8 × 10 – 4 . BER error rates are higher when excess incorrect dNTPs are included in the reaction or when wild type DNA polymerase β is replaced by DNA polymerase β variants that fill single nucleotide gaps with lower fidelity. Under these conditions, the base substitution fidelity of polymerase β-dependent BER is 3–8-fold higher than is single nucleotide gap filling by polymerase β alone. Thus other proteins in the BER reaction may enhance the base substitution fidelity of DNA polymerase β during single nucleotide BER.
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Extrinsic exonucleolytic proofreading could improve the fidelity of Pol α during initiation of Okazaki fragments, the fidelity of Pol η at a replication fork, or the fidelity of Pol β during single-nucleotide BER.
“For example, extrinsic exonucleolytic proofreading could improve the fidelity of Pol ␣ (51) during initiation of Okazaki fragments, the fidelity of Pol at a replication fork (52), or the fidelity of Pol  during single-nucleotide BER (53).”
From DNA Replication Fidelity (2004) · cites this paper as [53]
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- Authors
- Matsuda, T., Vande Berg, B. J., Bebenek, K., Osheroff, W. P., Wilson, S. H., & Kunkel, T. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Kunkel, Thomas A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-07
- Volume
- 278
- Issue
- 28
- Pages
- 25947-25951
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1972717311
- Cited by
- 35
- References
- 31
- Citations by year
- 2022: 1 · 2021: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 1.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- 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
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- base excision repair, DNA polymerase beta, uracil-DNA glycosylase, AP endonuclease, LIG1, dNTP incorporation
- MeSH terms
- DNA Ligase ATP, Amino Acid Sequence, Base Sequence, DNA, DNA Repair, Escherichia coli, Humans, Molecular Sequence Data, N-Glycosyl Hydrolases, Oligonucleotides, DNA Ligases, Carbon-Oxygen Lyases, DNA Polymerase beta, Base Pair Mismatch, DNA-(Apurinic or Apyrimidinic Site) Lyase, DNA Glycosylases, Uracil-DNA Glycosidase
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