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Engineered CRISPR-OsCas12f1 and RhCas12f1 with robust activities and expanded target range for genome editing. | LitMetric

AI Article Synopsis

  • The type V-F CRISPR-Cas12f system shows great potential for therapy due to its small Cas12f proteins, making it a suitable option for gene editing.
  • Researchers discovered six new Cas12f1 proteins that can edit genes in mammalian cells, with OsCas12f1 and RhCas12f1 demonstrating the most efficient editing abilities.
  • Enhanced versions of these proteins were created, improving their editing capabilities and potential applications in vivo, including epigenetic editing and gene activation in living organisms.

Article Abstract

The type V-F CRISPR-Cas12f system is a strong candidate for therapeutic applications due to the compact size of the Cas12f proteins. In this work, we identify six uncharacterized Cas12f1 proteins with nuclease activity in mammalian cells from assembled bacterial genomes. Among them, OsCas12f1 (433 aa) from Oscillibacter sp. and RhCas12f1 (415 aa) from Ruminiclostridium herbifermentans, which respectively target 5' T-rich Protospacer Adjacent Motifs (PAMs) and 5' C-rich PAMs, show the highest editing activity. Through protein and sgRNA engineering, we generate enhanced OsCas12f1 (enOsCas12f1) and enRhCas12f1 variants, with 5'-TTN and 5'-CCD (D = not C) PAMs respectively, exhibiting much higher editing efficiency and broader PAMs, compared with the engineered variant Un1Cas12f1 (Un1Cas12f1_ge4.1). Furthermore, by fusing the destabilized domain with enOsCas12f1, we generate inducible-enOsCas12f1 and demonstate its activity in vivo by single adeno-associated virus delivery. Finally, dead enOsCas12f1-based epigenetic editing and gene activation can also be achieved in mammalian cells. This study thus provides compact gene editing tools for basic research with remarkable promise for therapeutic applications.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10090079PMC
http://dx.doi.org/10.1038/s41467-023-37829-7DOI Listing

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