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Series GSE154936 Query DataSets for GSE154936
Status Public on Sep 08, 2020
Title Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR/Cas9 screening and transcriptomics
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary The adenosine analogue remdesivir has emerged as a front-line antiviral treatment for SARS-CoV-2, with preliminary evidence that it reduces the duration and severity of illness. As clinical trials are ongoing, the full side effect profile of remdesivir is not yet known. Prior clinical studies have identified adverse events, and remdesivir has been shown to inhibit mitochondrial RNA polymerase in biochemical experiments, yet little is known about the specific genetic pathways involved in cellular remdesivir metabolism and cytotoxicity. Through genome-wide CRISPR/Cas9 screening (data not provided here) and RNA sequencing, we identify specific genes and pathways implicated in remdesivir metabolism. We show that remdesivir treatment leads to a global repression of mitochondrial respiratory activity. Further, we show that loss of the mitochondrial nucleoside transporter SLC29A3 or the mitochondrial adenylate kinase AK2 provide 10-72-fold mitigation of remdesivir toxicity while conserving its antiviral potency. This work provides candidate gene targets to reduce remdesivir toxicity and provides a proof-of-principle for the use of CRISPR/Cas9 screening to elucidate mechanisms of drug cytotoxicity.
 
Overall design RNA-sequencing of on liver and intestinal cell lines treated with remdesivir or Hydroxychloroquine (HCQ).


 
Contributor(s) Akinci E, Cha M, Hamilton MC, Lin L, Yeo GH, Bermudez-Cabrera HC, Zanetti LC, Velimirovic M, Khowpinitchai B, Fife JD, Sovrovic M, Jodhani R, Davey R, Cassa CA, Sherwood RI
Citation(s)
  • Akinci E, Cha M, Lin L, Yeo G et al. Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics. bioRxiv 2020 Aug 28. PMID: 32869031
Submission date Jul 22, 2020
Last update date Sep 08, 2020
Contact name Richard I Sherwood
Organization name Brighan and Women's Hospital and Harvard Medical School
Department Division of Genetics, Department of Medicine
Street address 77 Avenue Louis Pasteur
City Boston
State/province MA
ZIP/Postal code 02115
Country USA
 
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (24)
GSM4684605 HCT116, DMSO, 8h
GSM4684606 HCT116, DMSO, 24h
GSM4684607 HCT116, HCQ, 8h
Relations
BioProject PRJNA647903
SRA SRP273148

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Supplementary file Size Download File type/resource
GSE154936_raw_counts.csv.gz 721.6 Kb (ftp)(http) CSV
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Raw data are available in SRA
Processed data are available on Series record

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