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DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid
Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structur...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621889/ https://www.ncbi.nlm.nih.gov/pubmed/37920723 http://dx.doi.org/10.1016/j.xcrp.2023.101635 |
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author | Oyaghire, Stanley N. Quijano, Elias Perera, J. Dinithi R. Mandl, Hanna K. Saltzman, W. Mark Bahal, Raman Glazer, Peter M. |
author_facet | Oyaghire, Stanley N. Quijano, Elias Perera, J. Dinithi R. Mandl, Hanna K. Saltzman, W. Mark Bahal, Raman Glazer, Peter M. |
author_sort | Oyaghire, Stanley N. |
collection | PubMed |
description | Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structural modification poses a challenge because of the inherent racemization risk in O-alkylation of the precursory serine side chain. To circumvent this risk and improve γPNA accessibility, we explore the utility of γPNA oligomers possessing the hydroxymethyl-γ moiety for gene-editing applications. We demonstrate that a γPNA oligomer possessing the hydroxymethyl modification, despite weaker preorganization, retains the ability to form a hybrid with the double-stranded DNA target of comparable stability and with higher affinity than that of the diethylene glycol-γPNA. When formulated into poly(lactic-co-glycolic acid) nanoparticles, the hydroxymethyl-γPNA stimulates higher frequencies (≥ 1.5-fold) of gene modification than the diethylene glycol γPNA in mouse bone marrow cells. |
format | Online Article Text |
id | pubmed-10621889 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-106218892023-11-02 DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid Oyaghire, Stanley N. Quijano, Elias Perera, J. Dinithi R. Mandl, Hanna K. Saltzman, W. Mark Bahal, Raman Glazer, Peter M. Cell Rep Phys Sci Article Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structural modification poses a challenge because of the inherent racemization risk in O-alkylation of the precursory serine side chain. To circumvent this risk and improve γPNA accessibility, we explore the utility of γPNA oligomers possessing the hydroxymethyl-γ moiety for gene-editing applications. We demonstrate that a γPNA oligomer possessing the hydroxymethyl modification, despite weaker preorganization, retains the ability to form a hybrid with the double-stranded DNA target of comparable stability and with higher affinity than that of the diethylene glycol-γPNA. When formulated into poly(lactic-co-glycolic acid) nanoparticles, the hydroxymethyl-γPNA stimulates higher frequencies (≥ 1.5-fold) of gene modification than the diethylene glycol γPNA in mouse bone marrow cells. 2023-10-18 /pmc/articles/PMC10621889/ /pubmed/37920723 http://dx.doi.org/10.1016/j.xcrp.2023.101635 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Oyaghire, Stanley N. Quijano, Elias Perera, J. Dinithi R. Mandl, Hanna K. Saltzman, W. Mark Bahal, Raman Glazer, Peter M. DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid |
title | DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid |
title_full | DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid |
title_fullStr | DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid |
title_full_unstemmed | DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid |
title_short | DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid |
title_sort | dna recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621889/ https://www.ncbi.nlm.nih.gov/pubmed/37920723 http://dx.doi.org/10.1016/j.xcrp.2023.101635 |
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