ArticleProceedings of the National Academy of Sciences of the United States of America2015
Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
34 citing papers in PubMed, 57 citations in OpenAlex.
- Substrate energetics in non-templated DNA synthesis by terminal deoxynucleotidyl transferase.Nucleic acids research · 2026Article
- Atomistic Simulations Decode the Mechanisms of DNA and RNA Processing Enzymes: Function through Motion.Accounts of chemical research · 2026Article
- The Enzymatic Mechanism of OAS: How Metal Ions and Quantum Effects Help Activate Innate Immunity.ACS omega · 2026Article
- Structural basis of transcription: RNA polymerase II substrate binding and metal coordination using a free-electron laser.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Effects of the Y432S Cancer-Associated Variant on the Reaction Mechanism of Human DNA Polymerase κ.Journal of chemical information and modeling · 2024Article
- In crystallo observation of active site dynamics and transient metal ion binding within DNA polymerases.Structural dynamics (Melville, N.Y.) · 2023Article
- Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints.Nature communications · 2022Article
- In crystallo observation of three metal ion promoted DNA polymerase misincorporation.Nature communications · 2022Article
- Interlocking activities of DNA polymerase β in the base excision repair pathway.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair.Nature communications · 2021Article
- Controlled Trafficking of Multiple and Diverse Cations Prompts Nucleic Acid Hydrolysis.ACS catalysis · 2021Article
- Combining Evolutionary Conservation and Quantum Topological Analyses To Determine Quantum Mechanics Subsystems for Biomolecular Quantum Mechanics/Molecular Mechanics Simulations.Journal of chemical theory and computation · 2021Article
- Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide.Nature communications · 2021Article
- DNA polymerase β: Closing the gap between structure and function.DNA repair · 2020Review
- Article
- Recruiting Mechanism and Functional Role of a Third Metal Ion in the Enzymatic Activity of 5' Structure-Specific Nucleases.Journal of the American Chemical Society · 2020Article
- Extensive free-energy simulations identify water as the base in nucleotide addition by DNA polymerase.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Structural Basis of Transcription: RNA Polymerase Backtracking and Its Reactivation.Molecular cell · 2019Article
- Non-nucleoside Reverse Transcriptase Inhibitors Inhibit Reverse Transcriptase through a Mutually Exclusive Interaction with Divalent Cation-dNTP Complexes.Biochemistry · 2019Article
- Uncovering a unique approach for damaged DNA replication: A computational investigation of a mutagenic tobacco-derived thymine lesion.Nucleic acids research · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
DNA polymerases facilitate faithful insertion of nucleotides, a central reaction occurring during DNA replication and repair. DNA synthesis (forward reaction) is "balanced," as dictated by the chemical equilibrium by the reverse reaction of pyrophosphorolysis. Two closely spaced divalent metal ions (catalytic and nucleotide-binding metals) provide the scaffold for these reactions. The catalytic metal lowers the pKa of O3' of the growing primer terminus, and the nucleotide-binding metal facilitates substrate binding. Recent time-lapse crystallographic studies of DNA polymerases have identified an additional metal ion (product metal) associated with pyrophosphate formation, leading to the suggestion of its possible involvement in the reverse reaction. Here, we establish a rationale for a role of the product metal using quantum mechanical/molecular mechanical calculations of the reverse reaction in the confines of the DNA polymerase β active site. Additionally, site-directed mutagenesis identifies essential residues and metal-binding sites necessary for pyrophosphorolysis. The results indicate that the catalytic metal site must be occupied by a magnesium ion for pyrophosphorolysis to occur. Critically, the product metal site is occupied by a magnesium ion early in the pyrophosphorolysis reaction path but must be removed later. The proposed dynamic nature of the active site metal ions is consistent with crystallographic structures. The transition barrier for pyrophosphorolysis was estimated to be significantly higher than that for the forward reaction, consistent with kinetic activity measurements of the respective reactions. These observations provide a framework to understand how ions and active site changes could modulate the internal chemical equilibrium of a reaction that is central to genome stability.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.