Pentose Phosphate Pathway Function Affects Tolerance to the G-Quadruplex Binder TMPyP4

Andrew, Elizabeth J.; Merchan, Stephanie; Lawless, Conor; Banks, Adrian P.; Wilkinson, Darren J.; Lydall, David

doi:10.1371/journal.pone.0066242

Cited by 17 publications

(14 citation statements)

References 46 publications

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“…DIXY is an online data visualization tool for browsing QFA fitness plots, which show evidence for genetic interaction by comparing fitnesses of strains in a query screen with fitnesses in a control screen ( Addinall et al 2011 ). QFA screen data presented in this paper along with data from ( Andrew et al 2013 ) can be visualized here: http://bsu-srv.ncl.ac.uk/dixy-pol/viz/ . Note that the DAmP alleles are missing from the data obtained in Andrew et al (2013) .…”

Section: Methodsmentioning

confidence: 99%

Genetic Networks Required to Coordinate Chromosome Replication by DNA Polymerases α, δ, and ε in Saccharomyces cerevisiae

Dubarry

Lawless

Banks

et al. 2015

G3 Genes|Genomes|Genetics

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Three major DNA polymerases replicate the linear eukaryotic chromosomes. DNA polymerase α-primase (Pol α) and DNA polymerase δ (Pol δ) replicate the lagging-strand and Pol α and DNA polymerase ε (Pol ε) the leading-strand. To identify factors affecting coordination of DNA replication, we have performed genome-wide quantitative fitness analyses of budding yeast cells containing defective polymerases. We combined temperature-sensitive mutations affecting the three replicative polymerases, Pol α, Pol δ, and Pol ε with genome-wide collections of null and reduced function mutations. We identify large numbers of genetic interactions that inform about the roles that specific genes play to help Pol α, Pol δ, and Pol ε function. Surprisingly, the overlap between the genetic networks affecting the three DNA polymerases does not represent the majority of the genetic interactions identified. Instead our data support a model for division of labor between the different DNA polymerases during DNA replication. For example, our genetic interaction data are consistent with biochemical data showing that Pol ε is more important to the Pre-Loading complex than either Pol α or Pol δ. We also observed distinct patterns of genetic interactions between leading- and lagging-strand DNA polymerases, with particular genes being important for coupling proliferating cell nuclear antigen loading/unloading (Ctf18, Elg1) with nucleosome assembly (chromatin assembly factor 1, histone regulatory HIR complex). Overall our data reveal specialized genetic networks that affect different aspects of leading- and lagging-strand DNA replication. To help others to engage with these data we have generated two novel, interactive visualization tools, DIXY and Profilyzer.

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Section: Methodsmentioning

confidence: 99%

Genetic Networks Required to Coordinate Chromosome Replication by DNA Polymerases α, δ, and ε in Saccharomyces cerevisiae

Dubarry

Lawless

Banks

et al. 2015

G3 Genes|Genomes|Genetics

Self Cite

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“…In addition, TMPyP4 can also interact with some G-rich sequences and stabilize i-motif structures that promote the formation of G-quadruplexes [89, 90. TMPyP4 is thus a promising agent as a lead compound for a novel anti-cancer therapy targeting G-quadruplexes 91 . Owing to the poor selectivity of TMPyP4, however, TMPyP4 itself cannot be used as a therapeutic.…”

Section: C-myc As a Therapeutic Targetmentioning

confidence: 99%

Small Molecules Targeting c-Myc Oncogene: Promising Anti-Cancer Therapeutics

et al. 2014

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The nuclear transcription factor c-Myc is a member of the Myc gene family with multiple functions and located on band q24.1 of chromosome 8. The c-Myc gene is activated by chromosomal translocation, rearrangement, and amplification. Its encoded protein transduces intracellular signals to the nucleus, resulting in the regulation of cell proliferation, differentiation, and apoptosis, and has the ability to transform cells and bind chromosomal DNA. c-Myc also plays a critical role in malignant transformation. The abnormal over-expression of c-Myc is frequently observed in some tumors, including carcinomas of the breast, colon, and cervix, as well as small-cell lung cancer, osteosarcomas, glioblastomas, and myeloid leukemias, therefore making it a possible target for anticancer therapy. In this minireview, we summarize unique characteristics of c-Myc and therapeutic strategies against cancer using small molecules targeting the oncogene, and discuss the prospects in the development of agents targeting c-Myc, in particular G-quadruplexes formed in c-Myc promoter and c-Myc/Max dimerization. Such information will be of importance for the research and development of c-Myc-targeted drugs.

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“…Previous studies have shown that TMPyP4 can induce calcium release by direct interaction with the Ca2+ release protein from sarcoplasmic reticulum [51]. Furthermore, studies in yeast suggest that TMPyP4 can induce a cellular oxidative stress response that could affect calcium homeostasis [52]. TMPyP4 rescue of calcium homeostasis in premutation fibroblasts could theoretically involve similar mechanisms.…”

Section: Discussionmentioning

confidence: 99%

CGG Repeats in the 5’UTR of FMR1 RNA Regulate Translation of Other RNAs Localized in the Same RNA Granules

Rovozzo¹,

Korza²,

Baker³

et al. 2016

PLoS ONE

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CGG repeats in the 5’UTR of Fragile X Mental Retardation 1 (FMR1) RNA mediate RNA localization and translation in granules. Large expansions of CGG repeats (> 200 repeats) in FMR1, referred to as full mutations, are associated with fragile X syndrome (FXS). Smaller expansions (55–200 repeats), referred to as premutations, are associated with fragile X tremor ataxia syndrome (FXTAS) and fragile X premature ovarian insufficiency (FXPOI). TMPyP4 is a porphyrin ring compound that destabilizes CGG repeat RNA secondary structure. Here we show that exogenous CGG repeat RNA by itself, lacking the FMRP ORF, microinjected into hippocampal neurons is localized in RNA granules and inhibits translation of ARC RNA, which is localized in the same granules. TMPyP4 rescues translation of ARC RNA in granules. We also show that in human premutation fibroblasts with endogenous CGG repeat expansions in the FMR1 gene, translation of ARC RNA is inhibited and calcium homeostasis is disrupted and both phenotypes are rescued by TMPyP4. Inhibition of granule translation by expanded CGG repeats and rescue of granule translation by TMPy4, represent potential pathogenic mechanism and therapeutic strategy, respectively, for FXTAS and FXPOI.

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Pentose Phosphate Pathway Function Affects Tolerance to the G-Quadruplex Binder TMPyP4

Cited by 17 publications

References 46 publications

Genetic Networks Required to Coordinate Chromosome Replication by DNA Polymerases α, δ, and ε in Saccharomyces cerevisiae

Genetic Networks Required to Coordinate Chromosome Replication by DNA Polymerases α, δ, and ε in Saccharomyces cerevisiae

Small Molecules Targeting c-Myc Oncogene: Promising Anti-Cancer Therapeutics

CGG Repeats in the 5’UTR of FMR1 RNA Regulate Translation of Other RNAs Localized in the Same RNA Granules

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