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Updated: May 10, 2026

In Vitro Chemical Mapping of G-Quadruplex DNA Structures by Bis-3-Chloropiperidines
05:32

In Vitro Chemical Mapping of G-Quadruplex DNA Structures by Bis-3-Chloropiperidines

Published on: May 12, 2023

Pentose phosphate pathway function affects tolerance to the G-quadruplex binder TMPyP4

Elizabeth J Andrew1, Stephanie Merchan, Conor Lawless

  • 1Institute for Cell and Molecular Biosciences, Newcastle University Medical School, Newcastle Upon Tyne, United Kingdom.

Plos One
|June 19, 2013
PubMed

Insights

The anti-cancer drug candidate TMPyP4 causes light-dependent oxidative stress in yeast, not G-quadruplex binding. This finding impacts the drug

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • G-quadruplexes are DNA structures found in guanine-rich regions, particularly at telomeres.
  • Ligands like TMPyP4 stabilize G-quadruplexes and are investigated as anti-cancer agents.
  • Understanding TMPyP4's in vivo mechanism is crucial for its therapeutic potential.

Purpose of the Study:

  • To elucidate the in vivo mechanism of action of the G-quadruplex ligand TMPyP4.
  • To identify cellular pathways involved in TMPyP4 sensitivity using a genome-wide screen in Saccharomyces cerevisiae.

Main Methods:

  • Conducted a genome-wide screen in budding yeast (Saccharomyces cerevisiae) to identify genes affecting TMPyP4 sensitivity.
  • Assessed sensitivity to TMPyP4, hydrogen peroxide, RHPS4, and hydroxyurea in gene deletion strains.
  • Investigated the role of the pentose phosphate pathway (PPP) and oxidative stress response genes (CCS1, YAP1).

Main Results:

  • Deletion of key pentose phosphate pathway (PPP) genes increased yeast sensitivity to TMPyP4.
  • Sensitivity to TMPyP4 was also elevated in strains lacking oxidative stress response genes (CCS1, YAP1).
  • TMPyP4-sensitive strains showed cross-sensitivity to hydrogen peroxide, suggesting a role for oxidative stress.

Conclusions:

  • TMPyP4 treatment induces a light-dependent oxidative stress response in budding yeast.
  • Oxidative stress, rather than direct G-quadruplex binding, appears to be the primary mechanism of TMPyP4 cytotoxicity.
  • Findings have significant implications for the therapeutic application and understanding of TMPyP4's mechanism of action.

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