Academic Journal
Megabase-scale human genome rearrangement with programmable bridge recombinases.
| Τίτλος: | Megabase-scale human genome rearrangement with programmable bridge recombinases. |
|---|---|
| Συγγραφείς: | Perry NT; Arc Institute, Palo Alto, CA, USA.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.; University of California, Berkeley - University of California, San Francisco, Graduate Program in Bioengineering, Berkeley, CA, USA., Bartie LJ; Arc Institute, Palo Alto, CA, USA.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.; University of California, Berkeley - University of California, San Francisco, Graduate Program in Bioengineering, Berkeley, CA, USA., Katrekar D; Arc Institute, Palo Alto, CA, USA., Gonzalez GA; Arc Institute, Palo Alto, CA, USA., Durrant MG; Arc Institute, Palo Alto, CA, USA., Pai JJ; Arc Institute, Palo Alto, CA, USA., Fanton A; Arc Institute, Palo Alto, CA, USA.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.; University of California, Berkeley - University of California, San Francisco, Graduate Program in Bioengineering, Berkeley, CA, USA., Martins JQ; Arc Institute, Palo Alto, CA, USA.; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA., Hiraizumi M; Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo, Japan., Ricci-Tam C; Arc Institute, Palo Alto, CA, USA., Nishimasu H; Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.; Structural Biology Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan.; Inamori Research Institute for Science, Shimogyo-ku, Kyoto, Japan., Konermann S; Arc Institute, Palo Alto, CA, USA.; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA., Hsu PD; Arc Institute, Palo Alto, CA, USA.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA. |
| Πηγή: | Science (New York, N.Y.) [Science] 2026 Mar 12; Vol. 391 (6790), pp. eadz0276. Date of Electronic Publication: 2026 Mar 12. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE |
| Imprint Name(s): | Publication: Original Publication: New York, N.Y. : [s.n.] 1880- |
| Ιατρικοί όροι (MeSH): | Recombinases*/genetics , Recombinases*/metabolism , DNA Nucleotidyltransferases*/genetics , DNA Nucleotidyltransferases*/metabolism , DNA Nucleotidyltransferases*/chemistry , Genome, Human* , Gene Rearrangement*, Escherichia coli/genetics ; DNA/genetics ; Humans ; Plasmids ; Genetic Engineering |
| Περίληψη: | Bridge recombinases are naturally occurring RNA-guided DNA recombinases that we previously demonstrated can programmably insert, excise, and invert DNA in vitro and in Escherichia coli. In this study, we report the discovery and engineering of the bridge recombinase ortholog ISCro4 for universal rearrangements of the human genome. We defined strategies for the optimal application of bridge systems, leveraging mechanistic insights to improve their targeting specificity. Through rational engineering of the ISCro4 bridge RNA and deep mutational scanning of its recombinase, we achieved up to 20% insertion efficiency into the human genome and genome-wide specificity as high as 82%. We further demonstrated intrachromosomal inversion and excision, mobilizing up to 0.93 megabases of DNA. Lastly, we provided proof of concept for plasmid-based excision of disease-relevant gene regulatory regions or repeat expansions. |
| Substance Nomenclature: | 0 (Recombinases) EC 2.7.7.- (DNA Nucleotidyltransferases) 9007-49-2 (DNA) |
| Entry Date(s): | Date Created: 20250925 Date Completed: 20260312 Latest Revision: 20260313 |
| Update Code: | 20260314 |
| DOI: | 10.1126/science.adz0276 |
| PMID: | 40997214 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1095-9203 |
|---|---|
| DOI: | 10.1126/science.adz0276 |