Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units

The understanding of the mechanisms behind nucleotide recognition by Argonaute 2, core protein of the RNA-induced silencing complex, is a key aspect in the optimization of small interfering RNAs (siRNAs) activity. To date, great efforts have been focused on the modification of certain regions of siR...

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Detalhes bibliográficos
Autores: Alagia, Adele, Terrazas, Montserrat, Eritja Casadellà, Ramón
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2015
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/126535
Acesso em linha:http://hdl.handle.net/10261/126535
Access Level:Acceso aberto
Palavra-chave:Ago2
RNAi
Central mismatched siRNA
siRNA
L-threoninol
On-/off-target effects
RISC
Silencing asymmetry
Single-stranded siRNA
Wobble base pair
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spelling Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) unitsAlagia, AdeleTerrazas, MontserratEritja Casadellà, RamónAgo2RNAiCentral mismatched siRNAsiRNAL-threoninolOn-/off-target effectsRISCSilencing asymmetrySingle-stranded siRNAWobble base pairThe understanding of the mechanisms behind nucleotide recognition by Argonaute 2, core protein of the RNA-induced silencing complex, is a key aspect in the optimization of small interfering RNAs (siRNAs) activity. To date, great efforts have been focused on the modification of certain regions of siRNA, such as the 3′/5′-termini and the seed region. Only a few reports have described the roles of central positions flanking the cleavage site during the silence process. In this study, we investigate the potential correlations between the thermodynamic and silencing properties of siRNA molecules carrying, at internal positions, an acyclic L-threoninol nucleic acid (aTNA) modification. Depending on position, the silencing is weakened or impaired. Furthermore, we evaluate the contribution of mismatches facing either a natural nucleotide or an aTNA modification to the siRNA potency. The position 11 of the antisense strand is more permissive to mismatches and aTNA modification, in respect to the position 10. Additionally, comparing the ON-/OFF-target silencing of central mismatched siRNAs with 5′-terminal modified siRNA, we concluded: (i) central perturbation of duplex pairing features weights more on potency rather than silencing asymmetry; (ii) complete bias for the ON-target silencing can be achieved with single L-threoninol modification near the 5'-end of the sense strand.This study was supported by the European Union (MULTIFUN, NMP4-LA-2011-262943), the Spanish Ministry of Education (CTQ2010-20541), Generalitat de Catalunya (2009/SGR/208). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. We are indebted to Dr. Elisa Pedone for her helpful advice and for providing technical assistance. We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).Peer reviewedMultidisciplinary Digital Publishing InstituteConsejo Superior de Investigaciones Científicas (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201520152015info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/126535reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésDOI: 10.3390/molecules20057602Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1265352026-05-22T06:33:51Z
dc.title.none.fl_str_mv Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units
title Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units
spellingShingle Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units
Alagia, Adele
Ago2
RNAi
Central mismatched siRNA
siRNA
L-threoninol
On-/off-target effects
RISC
Silencing asymmetry
Single-stranded siRNA
Wobble base pair
title_short Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units
title_full Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units
title_fullStr Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units
title_full_unstemmed Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units
title_sort Modulation of the RNA interference activity using central mismatched siRNAs and acyclic threoninol nucleic acids (aTNA) units
dc.creator.none.fl_str_mv Alagia, Adele
Terrazas, Montserrat
Eritja Casadellà, Ramón
author Alagia, Adele
author_facet Alagia, Adele
Terrazas, Montserrat
Eritja Casadellà, Ramón
author_role author
author2 Terrazas, Montserrat
Eritja Casadellà, Ramón
author2_role author
author
dc.contributor.none.fl_str_mv Consejo Superior de Investigaciones Científicas (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Ago2
RNAi
Central mismatched siRNA
siRNA
L-threoninol
On-/off-target effects
RISC
Silencing asymmetry
Single-stranded siRNA
Wobble base pair
topic Ago2
RNAi
Central mismatched siRNA
siRNA
L-threoninol
On-/off-target effects
RISC
Silencing asymmetry
Single-stranded siRNA
Wobble base pair
description The understanding of the mechanisms behind nucleotide recognition by Argonaute 2, core protein of the RNA-induced silencing complex, is a key aspect in the optimization of small interfering RNAs (siRNAs) activity. To date, great efforts have been focused on the modification of certain regions of siRNA, such as the 3′/5′-termini and the seed region. Only a few reports have described the roles of central positions flanking the cleavage site during the silence process. In this study, we investigate the potential correlations between the thermodynamic and silencing properties of siRNA molecules carrying, at internal positions, an acyclic L-threoninol nucleic acid (aTNA) modification. Depending on position, the silencing is weakened or impaired. Furthermore, we evaluate the contribution of mismatches facing either a natural nucleotide or an aTNA modification to the siRNA potency. The position 11 of the antisense strand is more permissive to mismatches and aTNA modification, in respect to the position 10. Additionally, comparing the ON-/OFF-target silencing of central mismatched siRNAs with 5′-terminal modified siRNA, we concluded: (i) central perturbation of duplex pairing features weights more on potency rather than silencing asymmetry; (ii) complete bias for the ON-target silencing can be achieved with single L-threoninol modification near the 5'-end of the sense strand.
publishDate 2015
dc.date.none.fl_str_mv 2015
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/126535
url http://hdl.handle.net/10261/126535
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv DOI: 10.3390/molecules20057602
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869419676371517440
score 15,812429

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