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5′-Modifications improve potency and efficacy of DNA donors for precision genome editing

Nuclease-directed genome editing is a powerful tool for investigating physiology and has great promise as a therapeutic approach to correct mutations that cause disease. In its most precise form, genome editing can use cellular homology-directed repair (HDR) pathways to insert information from an ex...

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Detalles Bibliográficos
Autores principales: Ghanta, Krishna S, Chen, Zexiang, Mir, Aamir, Dokshin, Gregoriy A, Krishnamurthy, Pranathi M, Yoon, Yeonsoo, Gallant, Judith, Xu, Ping, Zhang, Xiao-Ou, Ozturk, Ahmet Rasit, Shin, Masahiro, Idrizi, Feston, Liu, Pengpeng, Gneid, Hassan, Edraki, Alireza, Lawson, Nathan D, Rivera-Pérez, Jaime A, Sontheimer, Erik J, Watts, Jonathan K, Mello, Craig C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568340/
https://www.ncbi.nlm.nih.gov/pubmed/34665130
http://dx.doi.org/10.7554/eLife.72216
Descripción
Sumario:Nuclease-directed genome editing is a powerful tool for investigating physiology and has great promise as a therapeutic approach to correct mutations that cause disease. In its most precise form, genome editing can use cellular homology-directed repair (HDR) pathways to insert information from an exogenously supplied DNA-repair template (donor) directly into a targeted genomic location. Unfortunately, particularly for long insertions, toxicity and delivery considerations associated with repair template DNA can limit HDR efficacy. Here, we explore chemical modifications to both double-stranded and single-stranded DNA-repair templates. We describe 5′-terminal modifications, including in its simplest form the incorporation of triethylene glycol (TEG) moieties, that consistently increase the frequency of precision editing in the germlines of three animal models (Caenorhabditis elegans, zebrafish, mice) and in cultured human cells.