ArticleBiochemistry2013
Kinetic mechanism of DNA polymerization catalyzed by human DNA polymerase ε.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Conformational gating governs nucleotide incorporation by a DNA-crosslinked polymerase.Nucleic acids research · 2026Article
- Unprocessed genomic uracil as a source of DNA replication stress in cancer cells.Molecular cell · 2024Article
- Melanoma-Derived DNA Polymerase Theta Variants Exhibit Altered DNA Polymerase Activity.Biochemistry · 2024Article
- NMR measurements of transient low-populated tautomeric and anionic Watson-Crick-like G·T/U in RNA:DNA hybrids: implications for the fidelity of transcription and CRISPR/Cas9 gene editing.Nucleic acids research · 2024Article
- Article
- The iron-sulfur cluster is essential for DNA binding by human DNA polymerase ε.Scientific reports · 2022Article
- Efficient discrimination against RNA-containing primers by human DNA polymerase ε.Scientific reports · 2022Article
- Structural and Molecular Kinetic Features of Activities of DNA Polymerases.International journal of molecular sciences · 2022Review
- Kinetic investigation of the polymerase and exonuclease activities of human DNA polymerase ε holoenzyme.The Journal of biological chemistry · 2020Article
- Replication protein A binds RNA and promotes R-loop formation.The Journal of biological chemistry · 2020Article
- Article
- Activity and fidelity of human DNA polymerase α depend on primer structure.The Journal of biological chemistry · 2018Article
- Article
- Replication studies of carboxymethylated DNA lesions in human cells.Nucleic acids research · 2017Article
- Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands: Unique Detours around the Same Obstacle.Chemical reviews · 2017Review
- Elaborated Action of the Human Primosome.Genes · 2017Review
- Pre-steady-state Kinetic Analysis of a Family D DNA Polymerase from Thermococcus sp. 9°N Reveals Mechanisms for Archaeal Genomic Replication and Maintenance.The Journal of biological chemistry · 2015Article
- Evidence for the kinetic partitioning of polymerase activity on G-quadruplex DNA.Biochemistry · 2015Article
- Comparison of the kinetic parameters of the truncated catalytic subunit and holoenzyme of human DNA polymerase ɛ.DNA repair · 2015Article
- Yeast DNA polymerase ϵ catalytic core and holoenzyme have comparable catalytic rates.The Journal of biological chemistry · 2015Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Eukaryotes require highly accurate and processive DNA polymerases to ensure faithful and efficient replication of their genomes. DNA polymerase ε (Polε) has been shown to catalyze leading-strand DNA synthesis during replication in vivo, but little is known about the kinetic mechanism of polymerization catalyzed by this replicative enzyme. To elucidate this mechanism, we have generated a truncated, exonuclease-deficient mutant of the catalytic subunit of human Polε (Polε exo-) and carried out pre-steady-state kinetic analysis of this enzyme. Our results show that Polε exo-, as other DNA polymerases, follows an induced-fit mechanism when catalyzing correct nucleotide incorporation. Polε exo- binds DNA with a Kd(DNA) of 79 nM and dissociates from the E·DNA binary complex with a rate constant of 0.021 s(-1). Although Polε exo- binds a correct incoming nucleotide weakly with a Kd(dTTP) of 31 μM, it catalyzes correct nucleotide incorporation at a fast rate constant of 248 s(-1) at 20 °C. Both a large reaction amplitude difference (42%) between pulse-chase and pulse-quench assays and a small elemental effect (0.9) for correct dTTP incorporation suggest that a slow conformational change preceding the chemistry step limits the rate of correct nucleotide incorporation. In addition, our kinetic analysis shows that Polε exo- exhibits low processivity during polymerization. To catalyze leading-strand synthesis in vivo, Polε likely interacts with its three smaller subunits and additional replication factors in order to assemble a replication complex and significantly enhance its polymerization processivity.
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