ArticlePLoS genetics2017
Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons.
Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 77 citations in OpenAlex.
- DivergenteLife · 2026Article
- Wild strains reveal natural variation in C. elegans avoidance behaviors.G3 (Bethesda, Md.) · 2025Article
- Biosafety evaluation of etoposide lipid nanomedicines in C. elegans.Drug delivery and translational research · 2024Article
- Natural variation in protein kinase D modifies alcohol sensitivity inbioRxiv : the preprint server for biology · 2024Article
- CaeNDR, the Caenorhabditis Natural Diversity Resource.Nucleic acids research · 2024Article
- Beyond the reference: gene expression variation and transcriptional response to RNA interference in Caenorhabditis elegans.G3 (Bethesda, Md.) · 2023Article
- Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions.International journal of molecular sciences · 2023Article
- Cryptic genetic variation of expression quantitative trait locus architecture revealed by genetic perturbation in Caenorhabditis elegans.G3 (Bethesda, Md.) · 2023Article
- Interplay Between Polymorphic Short Tandem Repeats and Gene Expression Variation in Caenorhabditis elegans.Molecular biology and evolution · 2023Article
- Beyond the reference: gene expression variation and transcriptional response to RNAi inbioRxiv : the preprint server for biology · 2023Article
- A Single Nucleotide Variant in the PPARγ-homolog Eip75B Affects Fecundity in Drosophila.Molecular biology and evolution · 2023Article
- Praziquantel inhibits Caenorhabditis elegans development and species-wide differences might be cct-8-dependent.PloS one · 2023Article
- Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin.International journal for parasitology. Drugs and drug resistance · 2022Article
- Natural variation inGenome research · 2022Article
- Linkage mapping reveals loci that underlie differences in Caenorhabditis elegans growth.G3 (Bethesda, Md.) · 2022Article
- High-throughput small molecule screen identifies inhibitors of microsporidia invasion and proliferation in C. elegans.Nature communications · 2022Article
- Evaluating the power and limitations of genome-wide association studies in Caenorhabditis elegans.G3 (Bethesda, Md.) · 2022Article
- The impact of species-wide gene expression variation on Caenorhabditis elegans complex traits.Nature communications · 2022Article
- Review
- From QTL to gene: C. elegans facilitates discoveries of the genetic mechanisms underlying natural variation.Trends in genetics : TIG · 2021Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Many chemotherapeutic drugs are differentially effective from one patient to the next. Understanding the causes of this variability is a critical step towards the development of personalized treatments and improvements to existing medications. Here, we investigate sensitivity to a group of anti-neoplastic drugs that target topoisomerase II using the model organism Caenorhabditis elegans. We show that wild strains of C. elegans vary in their sensitivity to these drugs, and we use an unbiased genetic approach to demonstrate that this natural variation is explained by a methionine-to-glutamine substitution in topoisomerase II (TOP-2). The presence of a non-polar methionine at this residue increases hydrophobic interactions between TOP-2 and its poison etoposide, as compared to a polar glutamine. We hypothesize that this stabilizing interaction results in increased genomic instability in strains that contain a methionine residue. The residue affected by this substitution is conserved from yeast to humans and is one of the few differences between the two human topoisomerase II isoforms (methionine in hTOPIIα and glutamine in hTOPIIβ). We go on to show that this amino acid difference between the two human topoisomerase isoforms influences cytotoxicity of topoisomerase II poisons in human cell lines. These results explain why hTOPIIα and hTOPIIβ are differentially affected by various poisons and demonstrate the utility of C. elegans in understanding the genetics of drug responses.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.