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.
| Original language | English |
|---|---|
| Article number | 3061 |
| Journal | Nature Communications |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - 16 Jun 2020 |
Bibliographical note
Funding Information:The authors thank Adina Weinberger, Orna Dahan, Alexey Gritsenko, and Roni Rak for helpful discussions, Ronit Nir, Tali Avnit-Sagi, and Maya Lotan-Pompan for technical advice, and the Moshe Oren lab for advice and reagents. This work was supported by an EMBO long-term fellowship (to M.M.). E.S. is supported by the Crown Human Genome Center; the Else Kroener Fresenius Foundation; D.L. Schwarz; J.N. Halpern; L. Steinberg; J. Benattar; Aliza Moussaieff; Adelis Foundation; and grants funded by the European Research Council and the Israel Science Foundation.
Publisher Copyright:
© 2020, The Author(s).
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- General
- Physics and Astronomy (all)
