Academic Journal
Structural mechanism governing the directionality of bridge recombination.
| Τίτλος: | Structural mechanism governing the directionality of bridge recombination. |
|---|---|
| Συγγραφείς: | Hiraizumi M; Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan., Athukoralage JS; Arc Institute, Palo Alto, CA, USA., Perry NT; Arc Institute, Palo Alto, CA, USA.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.; San Francisco Graduate Program in Bioengineering, University of California, Berkeley, Berkeley, CA, USA., Tsujimoto E; Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan., Shiojiri N; Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan., Nagahata N; Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan., Lee L; Arc Institute, Palo Alto, CA, USA., Sun G; Arc Institute, Palo Alto, CA, USA., Durrant MG; Arc Institute, Palo Alto, CA, USA.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA., Chandrasekaran SS; Arc Institute, Palo Alto, CA, USA., Konermann S; Arc Institute, Palo Alto, CA, USA.; Department of Biochemistry, School of Medicine, Stanford University, Stanford, CA, USA., Yamashita K; Structural Biology Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan., Hsu PD; Arc Institute, Palo Alto, CA, USA. patrick@arcinstitute.org.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA. patrick@arcinstitute.org.; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA. patrick@arcinstitute.org.; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA. patrick@arcinstitute.org., Nishimasu H; Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan. nisimasu@g.ecc.u-tokyo.ac.jp.; Structural Biology Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. nisimasu@g.ecc.u-tokyo.ac.jp.; Inamori Research Institute for Science, Kyoto, Japan. nisimasu@g.ecc.u-tokyo.ac.jp. |
| Πηγή: | Nature [Nature] 2026 Oct; Vol. 658 (8134), pp. 269-278. Date of Electronic Publication: 2026 Aug 12. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| Imprint Name(s): | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| Ιατρικοί όροι (MeSH): | Escherichia coli*/genetics , Escherichia coli*/enzymology , DNA Transposable Elements*/genetics , Recombinases*/metabolism , Recombinases*/chemistry , Recombinases*/ultrastructure , Recombination, Genetic* , Cryoelectron Microscopy*, DNA, Circular/genetics ; DNA, Circular/chemistry ; DNA, Circular/metabolism ; DNA, Circular/ultrastructure ; DNA/chemistry ; DNA/metabolism ; DNA/ultrastructure ; DNA/genetics ; Models, Molecular ; Substrate Specificity |
| Περίληψη: | Bridge recombinases from the IS110 family of transposons, such as IS621, associate with a bridge RNA (bRNA) to mediate programmable recombination between donor DNA and target DNA1,2. Although insertion is mediated by the recombinase-bRNA complex, it remains unknown how IS621 elements are excised from host genomes to form the circular DNA intermediates required for transposition. Here we show that bRNA is weakly expressed from IS621 loci in the Escherichia coli genome and that the IS621 recombinase-bRNA complex mediates excision less efficiently than insertion. Furthermore, we present the cryo-electron microscopy structures of the IS621 recombinase-bRNA complex bound to excision DNA substrates, providing mechanistic insights into the excision reaction. Similar to the previously reported donor- and target-bound insertion complex2, the excision complex comprises two recombinase dimers, each accommodating the target- and donor-binding loops of the bRNA. However, DNA recognition differs notably between the two complexes. Although the donor and target DNAs form a bent U-shape during insertion2, the excision substrates adopt linear conformations and bind across both bRNA loops, forming an X-shaped structure. This geometry reduces the efficiency of top-strand exchange and contributes to the naturally observed bias favouring insertion over excision. Despite these differences, the efficiencies of both reactions are similarly modulated by base pairing between specific dinucleotides in the bRNA, termed handshake guides, and the top strands of the DNA substrates. Overall, this study provides mechanistic insights into the complete IS110 transposition cycle and facilitates the optimal design of programmable bridge-editing applications. (© 2026. The Author(s).) |
| Competing Interests: | Competing interests: P.D.H. acknowledges outside interest in Stylus Medicine, Terrain Biosciences and Monet AI as a co-founder, serves on the board of directors at Stylus Medicine and the scientific advisory board at Amgen, and is a venture partner at Thrive Capital. M.G.D. acknowledges outside interest in Stylus Medicine. N.T.P., M.G.D. and P.D.H. are inventors on patent application no. PCT/US23/82192 submitted by the Arc Institute that covers bridge recombinase in human cells. M.H., J.S.A., N.T.P., M.G.D., P.D.H. and H.N. are inventors on patent application no. PCT/US25/12632 submitted by the Arc Institute that covers bRNA engineering. All other authors declare no competing interests. |
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| Substance Nomenclature: | 0 (DNA Transposable Elements) 0 (Recombinases) 0 (DNA, Circular) 9007-49-2 (DNA) |
| Entry Date(s): | Date Created: 20260812 Date Completed: 20260930 Latest Revision: 20261001 |
| Update Code: | 20261001 |
| DOI: | 10.1038/s41586-026-10903-y |
| PMID: | 42587149 |
| Βάση Δεδομένων: | MEDLINE |
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