Spontaneous mutations that confer resistance to 2-deoxyglucose act through Hxk2 and Snf1 pathways to regulate gene expression and HXT endocytosis

PLoS Genetics
Samantha R SonciniMartin C Schmidt

Abstract

Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Spontaneous mutations in S. cerevisiae that conferred resistance to 2-deoxyglucose were identified by whole genome sequencing. Missense alleles of the HXK2, REG1, GLC7 and SNF1 genes were shown to confer significant resistance to 2-deoxyglucose and all had the potential to alter the activity and or target selection of the Snf1 kinase signaling pathway. All three missense alleles in HXK2 resulted in significantly reduced catalytic activity. Addition of 2DG promotes endocytosis of the glucose transporter Hxt3. All but one of the 2DG-resistant strains reduced the 2DG-mediated hexose transporter endocytosis by increasing plasma membrane occupancy of the Hxt3 protein. Increased expression of the DOG (deoxyglucose) phosphatases has been associated with resistance to 2-deoxyglucose. Expression of both the DOG1 and DOG2 mRNA was elevated after treatment with 2-deoxyglucose but induction of these genes is not associated with 2DG-resistance. RNAseq analysis of the transcriptional response to 2DG showed large scale, genome-wide changes in mRNA ab...Continue Reading

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Citations

Nov 3, 2020·Current Genetics·Martin C Schmidt, Allyson F O'Donnell
Sep 6, 2020·Biochemical Pharmacology·Clotilde Laussel, Sébastien Léon

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Methods Mentioned

BETA
RNAseq
immunoprecipitation
two-hybrid
fluorescence microscopy
electrophoresis

Software Mentioned

Prism
CLC Genomics Workbench
kallisto
Elements
Adobe Photoshop
NIS
Odyssey
RNAseq
GraphPad

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