POLG A467T Substrate Crossover Is Not Identified by Marginal Kinetic Intervals

**Objective:** Determine which comparisons of PZL-A-treated human POLG A467T with untreated wild type survive a declared sensitivity set at the eight deposited dNTP concentrations. **Design:** Exploratory incremental reanalysis of published active-complex-normalized incorporation summaries and existing Michaelis–Menten fits, using exact equality and the Cartesian product of four marginal kinetic intervals. **Results:** The deposited point fits give equality at 0.389815 µM dNTP. Nine of sixteen endpoint scenarios cross at positive substrate, but other allowed scenarios never cross. Monotonicity gives continuous-box ratio bounds without treating corner frequencies as probabilities. Every box curve is below untreated wild type for substrate greater than 8.331306 µM; only 10 µM among the eight deposited conditions meets that criterion. None guarantees above-WT incorporation. At 10 µM the point ratio is 0.6405 and the box range is 0.4180–0.9680. **Conclusions:** The marginal summaries identify a conditional below-WT direction at 10 µM, while they do not identify a persistent low-substrate crossover. Joint-fit covariance and active-complex normalization uncertainty remain unavailable; this sensitivity envelope is not a confidence region, a correction of the source analysis, or evidence of cellular restoration.

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Publication Details

Journal
Zenodo (CERN European Organization for Nuclear Research)
Published
2026-11-08
DOI
https://doi.org/10.5281/zenodo.24056765
Primary Topic
DNA Repair Mechanisms
Type
article
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article

POLG A467T Substrate Crossover Is Not Identified by Marginal Kinetic Intervals

Andrew Friedl
Zenodo (CERN European Organization for Nuclear Research)
DNA Repair Mechanisms
article

POLG A467T Substrate Crossover Is Not Identified by Marginal Kinetic Intervals

Andrew Friedl
article en

Abstract

**Objective:** Determine which comparisons of PZL-A-treated human POLG A467T with untreated wild type survive a declared sensitivity set at the eight deposited dNTP concentrations. **Design:** Exploratory incremental reanalysis of published active-complex-normalized incorporation summaries and existing Michaelis–Menten fits, using exact equality and the Cartesian product of four marginal kinetic intervals. **Results:** The deposited point fits give equality at 0.389815 µM dNTP. Nine of sixteen endpoint scenarios cross at positive substrate, but other allowed scenarios never cross. Monotonicity gives continuous-box ratio bounds without treating corner frequencies as probabilities. Every box curve is below untreated wild type for substrate greater than 8.331306 µM; only 10 µM among the eight deposited conditions meets that criterion. None guarantees above-WT incorporation. At 10 µM the point ratio is 0.6405 and the box range is 0.4180–0.9680. **Conclusions:** The marginal summaries identify a conditional below-WT direction at 10 µM, while they do not identify a persistent low-substrate crossover. Joint-fit covariance and active-complex normalization uncertainty remain unavailable; this sensitivity envelope is not a confidence region, a correction of the source analysis, or evidence of cellular restoration.

Zenodo (CERN European Organization for Nuclear Research)
DNA Repair Mechanisms
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