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CRISPR screening reveals a dependency on ribosome recycling for efficient SARS-CoV-2 programmed ribosomal frameshifting and viral replication.
Rehfeld, Frederick; Eitson, Jennifer L; Ohlson, Maikke B; Chang, Tsung-Cheng; Schoggins, John W; Mendell, Joshua T.
  • Rehfeld F; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Eitson JL; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Ohlson MB; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Chang TC; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Schoggins JW; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Mendell JT; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Sout
Cell Rep ; 42(2): 112076, 2023 Jan 30.
Article in English | MEDLINE | ID: covidwho-2209950
ABSTRACT
During translation of the genomic RNA of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus in the COVID-19 pandemic, host ribosomes undergo programmed ribosomal frameshifting (PRF) at a conserved structural element. Although PRF is essential for coronavirus replication, host factors that regulate this process have not yet been identified. Here we perform genome-wide CRISPR-Cas9 knockout screens to identify regulators of SARS-CoV-2 PRF. These screens reveal that loss of ribosome recycling factors markedly decreases frameshifting efficiency and impairs SARS-CoV-2 viral replication. Mutational studies support a model wherein efficient removal of ribosomal subunits at the ORF1a stop codon is required for frameshifting of trailing ribosomes. This dependency upon ribosome recycling is not observed with other non-pathogenic human betacoronaviruses and is likely due to the unique position of the ORF1a stop codon in the SARS clade of coronaviruses. These findings therefore uncover host factors that support efficient SARS-CoV-2 translation and replication.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Diagnostic study / Prognostic study / Screening_studies Language: English Journal: Cell Rep Year: 2023 Document Type: Article Affiliation country: J.celrep.2023.112076

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Diagnostic study / Prognostic study / Screening_studies Language: English Journal: Cell Rep Year: 2023 Document Type: Article Affiliation country: J.celrep.2023.112076