title: Pentose phosphate pathway function affects tolerance to the G-quadruplex binder TMPyP4.
abstract: G-quadruplexes form in guanine-rich regions of DNA and the presence of these structures at telomeres prevents the activity of telomerase in vitro. Ligands such as the cationic porphyrin TMPyP4 stabilise G-quadruplexes and are therefore under investigation for their potential use as anti-cancer drugs. In order to investigate the mechanism of action of TMPyP4 in vivo, we carried out a genome-wide screen in the budding yeast Saccharomyces cerevisiae. We found that deletion of key pentose phosphate pathway (PPP) genes increased the sensitivity of yeast to the presence of TMPyP4. The PPP plays an important role in the oxidative stress response and sensitivity to TMPyP4 also increased when genes involved in the oxidative stress response, CCS1 and YAP1, were deleted. For comparison we also report genome wide-screens using hydrogen peroxide, which causes oxidative stress, RHPS4, another G-quadruplex binder and hydroxyurea, an S phase poison. We found that a number of TMPyP4-sensitive strains are also sensitive to hydrogen peroxide in a genome-wide screen. Overall our results suggest that treatment with TMPyP4 results in light-dependent oxidative stress response in budding yeast, and that this, rather than G-quadruplex binding, is the major route to cytotoxicity. Our results have implications for the usefulness and mechanism of action of TMPyP4.
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University Medical School, Newcastle Upon Tyne, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Andrew
authors.forename: Stephanie
authors.initials: S
authors.lastname: Merchan
authors.forename: Conor
authors.initials: C
authors.lastname: Lawless
authors.forename: A Peter
authors.initials: AP
authors.lastname: Banks
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Wilkinson
authors.forename: David
authors.initials: D
authors.lastname: Lydall
mesh_terms: D000166:Acridines / Q000494:pharmacology; D055808:Drug Discovery; D054856:G-Quadruplexes; D017353:Gene Deletion; D056084:Genetic Fitness / Q000187:drug effects* / Q000528:radiation effects; D055106:Genome-Wide Association Study; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008027:Light; D008826:Microbial Sensitivity Tests; D018384:Oxidative Stress / Q000187:drug effects* / Q000528:radiation effects; D010427:Pentose Phosphate Pathway / Q000235:genetics / Q000502:physiology*; D011166:Porphyrins / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development* / Q000528:radiation effects
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D011166:Porphyrins; C021096:tetra(4-N-methylpyridyl)porphine; D006861:Hydrogen Peroxide