A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity
| Autor: | Doreen William, Jingyu Guo, Ilya Pound, John W. Rodgers, Michael Niederweis, John L. Hartman, Mert Icyuz, Brett A. McKinney, Sean M. Santos |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
gene–drug interaction Synthetic lethality Deoxycytidine genetic buffering 0302 clinical medicine cytarabine Gene Regulatory Networks Phenomics Genetics (clinical) 0303 health sciences Gene knockdown recursive expectation-maximization clustering (REMc) pharmacogenomics gemcitabine Nucleosides Deoxycytidine kinase 3. Good health Histone 030220 oncology & carcinogenesis Antimetabolites Antineoplastic Saccharomyces cerevisiae Proteins lcsh:QH426-470 DNA repair Saccharomyces cerevisiae Computational biology yeast phenomics Biology Article Chromatin remodeling 03 medical and health sciences Deoxycytidine Kinase Genetics Humans recursive expectation-maximization clustering (remc) quantitative high throughput cell array phenotyping (q-htcp) Gene 030304 developmental biology pharmacogenomics cell proliferation parameters (cpps) Epistasis Genetic biology.organism_classification High-Throughput Screening Assays lcsh:Genetics Gene Ontology 030104 developmental biology Pharmacogenetics Pharmacogenomics biology.protein quantitative high throughput cell array phenotyping (Q-HTCP) cell proliferation parameters (CPPs) gemcitabine |
| Zdroj: | Genes, Vol 10, Iss 10, p 770 (2019) Genes Volume 10 Issue 10 |
| DOI: | 10.1101/700153 |
| Popis: | Knowledge about synthetic lethality can be applied to enhance the efficacy of anticancer therapies in individual patients harboring genetic alterations in their cancer that specifically render it vulnerable. We investigated the potential for high-resolution phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, comprehensive, and quantitative assessment of drug&ndash gene interaction for gemcitabine and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures yet distinct antitumor efficacy. Human deoxycytidine kinase (dCK) was conditionally expressed in the Saccharomyces cerevisiae genomic library of knockout and knockdown (YKO/KD) strains, to globally and quantitatively characterize differential drug&ndash gene interaction for gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, histone modification, chromatin remodeling, and apoptosis-related processes influence gemcitabine specifically, while drug&ndash gene interaction specific to cytarabine was less enriched in gene ontology. Processes having influence over both drugs were DNA repair and integrity checkpoints and vesicle transport and fusion. Non-gene ontology (GO)-enriched genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics data were integrated to identify yeast&ndash human homologs with correlated differential gene expression and drug efficacy, thus providing a unique resource to predict whether differential gene expression observed in cancer genetic profiles are causal in tumor-specific responses to cytotoxic agents. |
| Databáze: | OpenAIRE |
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