mitoTev‐TALE: a monomeric DNA editing enzyme to reduce mutant mitochondrial DNA levels
| العنوان: | mitoTev‐TALE: a monomeric DNA editing enzyme to reduce mutant mitochondrial DNA levels |
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| المؤلفون: | David R. Edgell, Sandra R. Bacman, Claudia V. Pereira, Sion L. Williams, Carlos T. Moraes, Tania Arguello, Ugne Zekonyte |
| المصدر: | EMBO Molecular Medicine EMBO Molecular Medicine, Vol 10, Iss 9, Pp n/a-n/a (2018) |
| بيانات النشر: | EMBO, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Medicine (General), Mitochondrial DNA, DNA Repair, Mutant, monomeric, mitochondrial DNA, QH426-470, DNA, Mitochondrial, Viral Proteins, 03 medical and health sciences, chemistry.chemical_compound, R5-920, Transcription Activator-Like Effector Nucleases, Report, Genetics, Humans, heteroplasmy, Molecular Targeted Therapy, Gene, Cells, Cultured, Nuclease, biology, Hydrolysis, Point mutation, Wild type, Endonucleases, MERRF Syndrome, Recombinant Proteins, Heteroplasmy, mitoTev‐TALE, 030104 developmental biology, chemistry, I‐TevI, biology.protein, Molecular Medicine, Genetics, Gene Therapy & Genetic Disease, DNA, Protein Binding, Reports |
| الوصف: | Pathogenic mitochondrial DNA (mtDNA) mutations often co‐exist with wild‐type molecules (mtDNA heteroplasmy). Phenotypes manifest when the percentage of mutant mtDNA is high (70–90%). Previously, our laboratory showed that mitochondria‐targeted transcription activator‐like effector nucleases (mitoTALENs) can eliminate mutant mtDNA from heteroplasmic cells. However, mitoTALENs are dimeric and relatively large, making it difficult to package their coding genes into viral vectors, limiting their clinical application. The smaller monomeric GIY‐YIG homing nuclease from T4 phage (I‐TevI) provides a potential alternative. We tested whether molecular hybrids (mitoTev‐TALEs) could specifically bind and cleave mtDNA of patient‐derived cybrids harboring different levels of the m.8344A>G mtDNA point mutation, associated with myoclonic epilepsy with ragged‐red fibers (MERRF). We tested two mitoTev‐TALE designs, one of which robustly shifted the mtDNA ratio toward the wild type. When this mitoTev‐TALE was tested in a clone with high levels of the MERRF mutation (91% mutant), the shift in heteroplasmy resulted in an improvement of oxidative phosphorylation function. mitoTev‐TALE provides an effective architecture for mtDNA editing that could facilitate therapeutic delivery of mtDNA editing enzymes to affected tissues. |
| تدمد: | 1757-4684 1757-4676 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0e81273749e6a401c3af68d5471cb07dTest https://doi.org/10.15252/emmm.201708084Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0e81273749e6a401c3af68d5471cb07d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17574684 17574676 |
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