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Home / Equine Research Bank / J Mol Biol / Mechanism of translesion synthesis past an equine estrogen-D...
Journal of molecular biology2007; 371(5); 1151-1162; doi: 10.1016/j.jmb.2007.06.009

Mechanism of translesion synthesis past an equine estrogen-DNA adduct by Y-family DNA polymerases.

Abstract: 4-Hydroxyequilenin (4-OHEN)-dC is a major, potentially mutagenic DNA adduct induced by equine estrogens used for hormone replacement therapy. To study the miscoding property of 4-OHEN-dC and the involvement of Y-family human DNA polymerases (pols) eta, kappa and iota in that process, we incorporated 4-OHEN-dC into oligodeoxynucleotides and used them as templates in primer extension reactions catalyzed by pol eta, kappa and iota. Pol eta inserted dAMP opposite 4-OHEN-dC, accompanied by lesser amounts of dCMP and dTMP incorporation and base deletion. Pol kappa promoted base deletions as well as direct incorporation of dAMP and dCMP. Pol iota worked in conjunction with pol kappa, but not with pol eta, at a replication fork stalled by the adduct, resulting in increased dTMP incorporation. Our results provide a direct evidence that Y-family DNA pols can switch with one another during synthesis past the lesion. No direct incorporation of dGMP, the correct base, was observed with Y-family enzymes. The miscoding potency of 4-OHEN-dC may be associated with the development of reproductive cancers observed in women receiving hormone replacement therapy.
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Publication Date: 2007-06-09 PubMed ID: 17603077PubMed Central: PMC2039719DOI: 10.1016/j.jmb.2007.06.009Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article focuses on the study of how certain DNA polymerases interact with a particular DNA adduct that has been implicated in increasing the risk of reproductive cancers, specifically in women undergoing hormone replacement therapy.

Background

  • 4-Hydroxyequilenin (4-OHEN)-dC is a DNA adduct, or a piece of DNA bonded to a cancer-causing chemical, induced by equine estrogens. These estrogens are used in hormone replacement therapy.
  • This adduct is potentially mutagenic, meaning it may cause genetic changes that increase the risk of cancer.
  • The researchers were particularly interested in the way Y-family DNA polymerases interact with this adduct.
  • Y-family polymerases are a group of enzymes that play a significant role in DNA replication and repair, especially when the DNA structure is complex or damaged.

Methods

  • The researchers incorporated the 4-OHEN-dC adduct into oligodeoxynucleotides, small DNA molecules, and used them as templates in primer extension reactions.
  • These reactions were catalyzed by Y-family DNA polymerases – namely pol eta, kappa, and iota; and each of these polymerases was observed for its distinct interaction with the adduct.

Results

  • Pol eta incorporated another molecule, dAMP, opposite the adduct along with lesser amounts of two other molecules, dCMP and dTMP, and caused base deletion.
  • Pol kappa caused base deletions, and also induced direct incorporation of dAMP and dCMP.
  • Pol iota worked in conjunction with pol kappa, but not with pol eta when the replication was stalled by the adduct, resulting in increased incorporation of dTMP.
  • The researchers did not observe any direct incorporation of dGMP, the correct base, with any of the Y-family enzymes.
  • This indicates a potential switching between these polymerases when the replication process encounters such adducts.

Implications

  • The fact that these Y-family DNA polymerases did not directly incorporate the correct base suggests that the miscoding potency of the 4-OHEN-dC adduct may be linked to the development of reproductive cancers in women undergoing hormone replacement therapy.
  • This study provides crucial evidence about the molecular mechanisms underpinning DNA repair and replication, particularly in the context of cancer-risk DNA adducts and hormone replacement therapy.

Cite This Article

APA
Yasui M, Suzuki N, Liu X, Okamoto Y, Kim SY, Laxmi YR, Shibutani S. (2007). Mechanism of translesion synthesis past an equine estrogen-DNA adduct by Y-family DNA polymerases. J Mol Biol, 371(5), 1151-1162. https://doi.org/10.1016/j.jmb.2007.06.009

Publication

Journal of molecular biology
ISSN: 0022-2836
NlmUniqueID: 2985088R
Country: Netherlands
Language: English
Volume: 371
Issue: 5
Pages: 1151-1162

Researcher Affiliations

Yasui, Manabu
  • Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.
Suzuki, Naomi
    Liu, Xiaoping
      Okamoto, Yoshinori
        Kim, Sung Yeon
          Laxmi, Y R Santosh
            Shibutani, Shinya

              MeSH Terms

              • Animals
              • Base Sequence
              • Catalysis
              • DNA Adducts
              • DNA-Directed DNA Polymerase / chemistry
              • Equilenin / chemistry
              • Equilin / chemistry
              • Estrogens / chemistry
              • Female
              • Hormone Replacement Therapy / methods
              • Horses
              • Humans
              • Kinetics
              • Models, Chemical
              • Molecular Sequence Data

              Grant Funding

              • R01 ES012408 / NIEHS NIH HHS
              • R01 ES012408-02 / NIEHS NIH HHS
              • R01 ES012408-03 / NIEHS NIH HHS
              • ES012408 / NIEHS NIH HHS

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