Coiled-coil heterodimer-based recruitment of an exonuclease to CRISPR/Cas for enhanced gene editing.


Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
23 06 2022
Historique:
received: 19 07 2021
accepted: 16 06 2022
entrez: 23 6 2022
pubmed: 24 6 2022
medline: 28 6 2022
Statut: epublish

Résumé

The CRISPR/Cas system has emerged as a powerful and versatile genome engineering tool, revolutionizing biological and biomedical sciences, where an improvement of efficiency could have a strong impact. Here we present a strategy to enhance gene editing based on the concerted action of Cas9 and an exonuclease. Non-covalent recruitment of exonuclease to Cas9/gRNA complex via genetically encoded coiled-coil based domains, termed CCExo, recruited the exonuclease to the cleavage site and robustly increased gene knock-out due to progressive DNA strand recession at the cleavage site, causing decreased re-ligation of the nonedited DNA. CCExo exhibited increased deletion size and enhanced gene inactivation efficiency in the context of several DNA targets, gRNA selection, Cas variants, tested cell lines and type of delivery. Targeting a sequence-specific oncogenic chromosomal translocation using CCExo in cells of chronic myelogenous leukemia patients and in an animal model led to the reduction or elimination of cancer, establishing it as a highly specific tool for treating CML and potentially other appropriate diseases with genetic etiology.

Identifiants

pubmed: 35739111
doi: 10.1038/s41467-022-31386-1
pii: 10.1038/s41467-022-31386-1
pmc: PMC9226073
doi:

Substances chimiques

RNA, Guide 0
Exonucleases EC 3.1.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3604

Informations de copyright

© 2022. The Author(s).

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Auteurs

Duško Lainšček (D)

Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana, 1000, Slovenia.
EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, Ljubljana, 1000, Slovenia.

Vida Forstnerič (V)

Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana, 1000, Slovenia.

Veronika Mikolič (V)

Department of Hematology, Division of Internal Medicine, University Medical Centre Ljubljana, Zaloška 7, Ljubljana, 1000, Slovenia.
Graduate School of Biomedicine, University of Ljubljana, Ljubljana, 1000, Slovenia.

Špela Malenšek (Š)

Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana, 1000, Slovenia.
Graduate School of Biomedicine, University of Ljubljana, Ljubljana, 1000, Slovenia.

Peter Pečan (P)

Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana, 1000, Slovenia.
Graduate School of Biomedicine, University of Ljubljana, Ljubljana, 1000, Slovenia.

Mojca Benčina (M)

Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana, 1000, Slovenia.
EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, Ljubljana, 1000, Slovenia.

Matjaž Sever (M)

Department of Hematology, Division of Internal Medicine, University Medical Centre Ljubljana, Zaloška 7, Ljubljana, 1000, Slovenia.
Faculty of Medicine, University of Ljubljana, Korytkova 2, Ljubljana, 1000, Slovenia.

Helena Podgornik (H)

Department of Hematology, Division of Internal Medicine, University Medical Centre Ljubljana, Zaloška 7, Ljubljana, 1000, Slovenia.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia.

Roman Jerala (R)

Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana, 1000, Slovenia. roman.jerala@ki.si.
EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, Ljubljana, 1000, Slovenia. roman.jerala@ki.si.

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