Cited by 76DNA Repair MechanismsDNA and Nucleic Acid ChemistryGenetic factors in colorectal cancer

Proofreading of DNA Polymerase η-dependent Replication Errors

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Bebenek, Katarzyna, Matsuda, Toshiro, Masutani, Chikahide, Hanaoka, Fumio, Kunkel, Thomas A.·2001·Journal of Biological Chemistry

Abstract

Human DNA polymerase eta, the product of the skin cancer susceptibility gene XPV, bypasses UV photoproducts in template DNA that block synthesis by other DNA polymerases. Pol eta lacks an intrinsic proofreading exonuclease and copies DNA with low fidelity, such that pol eta errors could contribute to mutagenesis unless they are corrected. Here we provide evidence that pol eta can compete with other human polymerases during replication of duplex DNA, and in so doing it lowers replication fidelity. However, we show that pol eta has low processivity and extends mismatched primer termini less efficiently than matched termini. These properties could provide an opportunity for extrinsic exonuclease(s) to proofread pol eta-induced replication errors. When we tested this hypothesis during replication in human cell extracts, pol eta-induced replication infidelity was found to be modulated by changing the dNTP concentration and to be enhanced by adding dGMP to a replication reaction. Both effects are classical hallmarks of exonucleolytic proofreading. Thus, pol eta is ideally suited for its role in reducing UV-induced mutagenesis and skin cancer risk, in that its relaxed base selectivity may facilitate efficient bypass of UV photoproducts, while subsequent proofreading by extrinsic exonuclease(s) may reduce its mutagenic potential.

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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 [52]

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Research works printed but not linked: 5

  1. Wang, Y. C., Maher, V. M., and McCormick, J. J. (1991) Proc. Natl. Acad. Sci.
  2. Johnson, R. E., Washington, M. T., Prakash, S., and Prakash, L. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 12224 -12226
  3. Friedberg, E. C., Feaver, W. J., and Gerlach, V. L. (2000) Proc. Natl. Acad. Sci.
  4. Roberts, J. D., and Kunkel, T. A. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 7064 -7068
  5. Roberts, J. D., Thomas, D. C., and Kunkel, T. A. (1991) Proc. Natl. Acad. Sci.

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Authors
Bebenek, K., Matsuda, T., Masutani, C., 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 Biological Chemistry
Publisher
Elsevier BV
Published
2001-01
Volume
276
Issue
4
Pages
2317-2320
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2045684550
Cited by
76
References
32
Citations by year
2025: 1 · 2024: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2012: 1
FWCI
3.72
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
  • 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
DNA polymerase eta, UV photoproducts, replication fidelity, exonuclease proofreading, polymerase processivity, dGMP, dNTP concentration, UV mutagenesis, skin cancer predisposition
MeSH terms
Y-Family DNA Polymerases, DNA-Directed DNA Polymerase, DNA Repair, DNA Replication, Exodeoxyribonucleases, Humans, Models, Genetic, Mutagenesis, Base Pair Mismatch

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