Next Generation of Genome Editing?

Researchers at the Arc Institute in the USA have developed an advanced genome design system that enables fundamental DNA rearrangements. In two articles published in June 2024 in the journal Nature, they report the first DNA recombinase that uses a non-coding RNA, called "bridging RNA", to specifically recognise and modify DNA segments.

Patrick Hsu, a former PhD student at Harvard University and now Assistant Professor of Bioengineering at the University of California, Berkeley, led the team. The research results were published in collaboration with Hiroshi Nishimasu from the University of Tokyo. The studies describe the dual recognition of target and donor DNA through programmable interactions with the bridging RNA.

Scientific background of genome design

Mobile genetic elements (MGEs) are DNA segments that can move within and between genomes. This variety of MGEs can be found in all cell types. Insertion sequence (IS) elements are particularly common in bacteria and archaea. The IS110 family consists of "cut-and-paste" MGEs that excise themselves from the genome and form circular DNA that is integrated into specific target sequences. These elements contain a gene for the recombinase enzyme and flanking DNA segments.

It has now been discovered that removal of the IS110 element restores a promoter that activates the expression of a structured non-coding RNA (ncRNA), which is bound by the recombinase. This ncRNA forms in two loops: one binds to the donor DNA, the other to the target DNA. Because of this bridging function, it was given the name "bridging RNA". Through direct base pairing interactions, the bispecific bridging RNA connects the target and donor DNA, which facilitates DNA recombination by the IS110 recombinase. Experiments also showed that each loop of the bridging RNA is independently programmable, allowing target and donor DNA sequences to be combined in any combination.

The discovery of this bridge recombination mechanism could create a new generation of programmable RNA-guided tools that go beyond existing RNA interference and CRISPR-based mechanisms, opening up new possibilities in genome design. So it remains exciting to see when we will hear about the next discovery or the first applications in the treatment of patients. Read the above-mentioned publications "Bridge RNAs direct programmable recombination of target and donor DNA" and "Structural mechanism of bridge RNA-guided recombination" on the Nature website.