Bridge RNAs direct programmable recombination of target and donor DNA

Matthew G. Durrant, Nicholas T. Perry, James J. Pai, Aditya R. Jangid, Januka S. Athukoralage, Masahiro Hiraizumi, John P. McSpedon, April Pawluk, Hiroshi Nishimasu, Silvana Konermann and Patrick D. Hsu ()
Additional contact information
Matthew G. Durrant: Arc Institute
Nicholas T. Perry: Arc Institute
James J. Pai: Arc Institute
Aditya R. Jangid: Arc Institute
Januka S. Athukoralage: Arc Institute
Masahiro Hiraizumi: University of Tokyo
John P. McSpedon: Arc Institute
April Pawluk: Arc Institute
Hiroshi Nishimasu: University of Tokyo
Silvana Konermann: Arc Institute
Patrick D. Hsu: Arc Institute

Nature, 2024, vol. 630, issue 8018, 984-993

Abstract: Abstract Genomic rearrangements, encompassing mutational changes in the genome such as insertions, deletions or inversions, are essential for genetic diversity. These rearrangements are typically orchestrated by enzymes that are involved in fundamental DNA repair processes, such as homologous recombination, or in the transposition of foreign genetic material by viruses and mobile genetic elements1,2. Here we report that IS110 insertion sequences, a family of minimal and autonomous mobile genetic elements, express a structured non-coding RNA that binds specifically to their encoded recombinase. This bridge RNA contains two internal loops encoding nucleotide stretches that base-pair with the target DNA and the donor DNA, which is the IS110 element itself. We demonstrate that the target-binding and donor-binding loops can be independently reprogrammed to direct sequence-specific recombination between two DNA molecules. This modularity enables the insertion of DNA into genomic target sites, as well as programmable DNA excision and inversion. The IS110 bridge recombination system expands the diversity of nucleic-acid-guided systems beyond CRISPR and RNA interference, offering a unified mechanism for the three fundamental DNA rearrangements—insertion, excision and inversion—that are required for genome design.

Date: 2024
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DOI: 10.1038/s41586-024-07552-4

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