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Revolutionary ‘Bridge RNA’ system unlocks precision genome editing capabilities

Researchers at the Arc Institute have unveiled a groundbreaking genetic engineering tool called the bridge recombinase mechanism, offering unprecedented precision in DNA recombination and rearrangement. The study, published in Nature [1], details the discovery of the first DNA recombinase that utilises a non-coding RNA for sequence-specific selection of target and donor DNA molecules.

This bridge RNA is programmable, allowing the user to specify any desired genomic target sequence and any donor DNA molecule to be inserted.

Programmable bridge RNA: A new frontier in genomic editing

The bridge RNA system, derived from insertion sequence 110 (IS110) elements, one of countless types of transposable elements – or “jumping genes” – that cut and paste themselves to move within and between microbial genomes. It represents a significant leap forward in biological programming.

Senior author Patrick Hsu, an Arc Institute Core Investigator and UC Berkeley Assistant Professor of Bioengineering, said: “The bridge RNA system is a fundamentally new mechanism for biological programming. “Bridge recombination can universally modify genetic material through sequence-specific insertion, excision, inversion, and more, enabling a word processor for the living genome beyond CRISPR.”

The bridge RNA, formed when IS110 excises itself from a genome, folds into two independently programmable loops. This bispecific guide molecule allows researchers to specify both target and donor DNA sequences, enabling insertion of any desired genetic cargo into any genomic location.

Impressive efficiency and specificity

In their experiments with E. coli, the team demonstrated over 60% insertion efficiency of a desired gene with over 94% specificity for the correct genomic location. This high level of precision and efficiency showcases the potential of the bridge recombinase system for future applications in genetic engineering and therapeutic interventions.

Structural insights and future implications

Complementing the functional studies, collaborators at the University of Tokyo used cryo-electron microscopy to elucidate the molecular structures of the recombinase-bridge RNA complex bound to target and donor DNA. These structural insights provide a deeper understanding of the recombination process and may guide future optimisations of the system.

The bridge recombinase mechanism offers several advantages over current genome editing technologies, including the ability to join both DNA strands without releasing cut DNA fragments. This characteristic potentially sidesteps a key limitation of existing methods and opens new avenues for genome design.

As research continues, the bridge recombinase system may herald a third generation of RNA-guided systems, expanding beyond the DNA and RNA cutting mechanisms of CRISPR and RNA interference (RNAi) to offer a unified mechanism for programmable DNA rearrangements. This breakthrough could have far-reaching implications for both basic research and clinical applications in the field of genetic engineering.

See video explanation of the new Bridge Recombination system:

1. Patrick Hsu, Matthew Durrant, Nick Perry, et. al. Bridge RNAs direct programmable recombination of target and donor DNA. Nature. 26 June 2024.

BridgeRNA 2

Patrick Hsu, Nick Perry and Matt Durrant discuss the newly discovered bridge recombinase mechanism. Credit: Ray Rudolph