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High-throughput interrogation of programmed ribosomal frameshifting in human cells

Author

Listed:
  • Martin Mikl

    (Department of Computer Science and Applied Mathematics
    Department of Molecular Cell Biology and Weizmann Institute of Science
    Department of Molecular Genetics, Weizmann Institute of Science
    Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mount Carmel)

  • Yitzhak Pilpel

    (Department of Molecular Genetics, Weizmann Institute of Science)

  • Eran Segal

    (Department of Computer Science and Applied Mathematics
    Department of Molecular Cell Biology and Weizmann Institute of Science)

Abstract

Programmed ribosomal frameshifting (PRF) is the controlled slippage of the translating ribosome to an alternative frame. This process is widely employed by human viruses such as HIV and SARS coronavirus and is critical for their replication. Here, we developed a high-throughput approach to assess the frameshifting potential of a sequence. We designed and tested >12,000 sequences based on 15 viral and human PRF events, allowing us to systematically dissect the rules governing ribosomal frameshifting and discover novel regulatory inputs based on amino acid properties and tRNA availability. We assessed the natural variation in HIV gag-pol frameshifting rates by testing >500 clinical isolates and identified subtype-specific differences and associations between viral load in patients and the optimality of PRF rates. We devised computational models that accurately predict frameshifting potential and frameshifting rates, including subtle differences between HIV isolates. This approach can contribute to the development of antiviral agents targeting PRF.

Suggested Citation

  • Martin Mikl & Yitzhak Pilpel & Eran Segal, 2020. "High-throughput interrogation of programmed ribosomal frameshifting in human cells," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16961-8
    DOI: 10.1038/s41467-020-16961-8
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