Error-promoting DNA synthesis in ovarian cancer cells ☆
- a Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, USA
- b City of Hope Beckman Research Institute, Department of Molecular Pharmacology, USA
- c Indiana University School of Medicine, Department of Medicine, USA
- d Indiana University School of Medicine, Department of Obstetrics and Gynecology, USA
- e City of Hope Beckman Research Institute, Department of Molecular and Cellular Biology, USA
Open Access
Highlights
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- The DNA replication apparatus of ovarian cancers has a DNA synthesis process that is error-promoting.
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- There is a DNA polymerase efficiency difference between non-malignant and ovarian cancer cells for specific types of nucleotide mismatches.
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- Systematic analysis of ovarian cancer DNA replication could uncover mechanisms that drive genetic damage accumulation and contribute to disease.
Abstract
Objective
The objective of this study is to determine whether an altered DNA replication process is responsible for some of genetic damage observed in ovarian cancer.
Methods
The replication fidelity of the DNA synthetic process was evaluated in both malignant and non-malignant human ovarian cells. The types of replication errors produced were identified. In addition, kinetic analyses of the efficiency of ovarian cancer DNA polymerases for misincorporating nucleotides were performed.
Results
We report for the first time that ovarian cancer cells harbor an error promoting DNA replication apparatus which contributes to the decrease in DNA synthetic fidelity exhibited by these cells. Our study also shows that the decrease in DNA replication fidelity was not a result of an increased DNA replication activity. In addition, it was observed that the higher rate of DNA replication errors does not result in significant differences in the type of DNA replication-errors made during the DNA replication process; just the relative abundance. A detailed kinetic analysis of the efficiency of misincorporating nucleotides demonstrated that the DNA polymerases within the ovarian cancer cells exhibited a significant propensity for creating purine–pyrimidine nucleotide mismatches relative to non-malignant ovarian cells, while being only slightly more efficient at incorrectly pairing a purine nucleotide with a purine nucleotide.
Conclusions
All together, these data suggest that the systematic analysis of the DNA replication process in ovarian cancer could uncover information on some of the molecular mechanisms that drive the accumulation of genetic damage, and probably contribute to the pathogenesis of the disease.
Keywords
- Ovarian cancer;
- DNA replication;
- Multiprotein complex;
- Replication fidelity
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