Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides

Due to their capability to transport chemicals or proteins into target cells, cell-penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine-rich CPPs often show toxicity for reasons that remain poorly understood. Using a (...

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Autores: Lafarga, Vanesa, Díaz López, Irene, Galarreta, Antonio, Hisaoka, Misaru, Zarzuela, Eduardo, Fernandez-Leiro, Rafael, Muñoz, Jaime, Fernández-Capetillo, Óscar, Sirozh, Oleksandra, Boskovic, Jasminka, Jovanovic, Bogdan, Stoecklin, Georg, Ventoso Bande, Iván José
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/711091
Acceso en línea:http://hdl.handle.net/10486/711091
https://dx.doi.org/10.15252/embj.2019103311
Access Level:acceso abierto
Palabra clave:ALS
arginine-rich peptides
chromatin
mRNA
protamine
Biología y Biomedicina / Biología
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spelling Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptidesLafarga, VanesaDíaz López, IreneGalarreta, AntonioHisaoka, MisaruZarzuela, EduardoFernandez-Leiro, RafaelMuñoz, JaimeFernández-Capetillo, ÓscarSirozh, OleksandraBoskovic, JasminkaJovanovic, BogdanStoecklin, GeorgVentoso Bande, Iván JoséALSarginine-rich peptideschromatinmRNAprotamineBiología y Biomedicina / BiologíaDue to their capability to transport chemicals or proteins into target cells, cell-penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine-rich CPPs often show toxicity for reasons that remain poorly understood. Using a (PR)n dipeptide repeat that has been linked to amyotrophic lateral sclerosis (ALS) as a model of an arginine-rich CPP, we here show that the presence of (PR)n leads to a generalized displacement of RNA- and DNA-binding proteins from chromatin and mRNA. Accordingly, any reaction involving nucleic acids, such as RNA transcription, translation, splicing and degradation, or DNA replication and repair, is impaired by the presence of the CPPs. Interestingly, the effects of (PR)n are fully mimicked by protamine, a small arginine-rich protein that displaces histones from chromatin during spermatogenesis. We propose that widespread coating of nucleic acids and consequent displacement of RNA- and DNA-binding factors from chromatin and mRNA accounts for the toxicity of arginine-rich CPPs, including those that have been recently associated with the onset of ALSWe would want to thank Drs. André Nussenzweig an Jordi Carreras‐Puigvert for insightful comments on the manuscript. Research was funded by Fundación Botín, by Banco Santander through its Santander Universities Global Division and by grants from the Spanish Ministry of Science, Innovation and Universities (RTI2018‐102204‐B‐I00, co‐financed with European FEDER funds) and the European Research Council (ERC‐617840) to OF; DKFZ NCT3.0 Integrative Project in Cancer Research grant (NCT3.0_2015.54 DysregPT) and SFB 1036/TP07 from the Deutsche Forschungsgemeinschaft to G.S.EMBO PressDepartamento de Biología MolecularFacultad de Ciencias20212021-07-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/711091https://dx.doi.org/10.15252/embj.2019103311reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7110912026-06-23T12:46:27Z
dc.title.none.fl_str_mv Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides
title Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides
spellingShingle Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides
Lafarga, Vanesa
ALS
arginine-rich peptides
chromatin
mRNA
protamine
Biología y Biomedicina / Biología
title_short Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides
title_full Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides
title_fullStr Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides
title_full_unstemmed Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides
title_sort Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides
dc.creator.none.fl_str_mv Lafarga, Vanesa
Díaz López, Irene
Galarreta, Antonio
Hisaoka, Misaru
Zarzuela, Eduardo
Fernandez-Leiro, Rafael
Muñoz, Jaime
Fernández-Capetillo, Óscar
Sirozh, Oleksandra
Boskovic, Jasminka
Jovanovic, Bogdan
Stoecklin, Georg
Ventoso Bande, Iván José
author Lafarga, Vanesa
author_facet Lafarga, Vanesa
Díaz López, Irene
Galarreta, Antonio
Hisaoka, Misaru
Zarzuela, Eduardo
Fernandez-Leiro, Rafael
Muñoz, Jaime
Fernández-Capetillo, Óscar
Sirozh, Oleksandra
Boskovic, Jasminka
Jovanovic, Bogdan
Stoecklin, Georg
Ventoso Bande, Iván José
author_role author
author2 Díaz López, Irene
Galarreta, Antonio
Hisaoka, Misaru
Zarzuela, Eduardo
Fernandez-Leiro, Rafael
Muñoz, Jaime
Fernández-Capetillo, Óscar
Sirozh, Oleksandra
Boskovic, Jasminka
Jovanovic, Bogdan
Stoecklin, Georg
Ventoso Bande, Iván José
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Biología Molecular
Facultad de Ciencias
dc.subject.none.fl_str_mv ALS
arginine-rich peptides
chromatin
mRNA
protamine
Biología y Biomedicina / Biología
topic ALS
arginine-rich peptides
chromatin
mRNA
protamine
Biología y Biomedicina / Biología
description Due to their capability to transport chemicals or proteins into target cells, cell-penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine-rich CPPs often show toxicity for reasons that remain poorly understood. Using a (PR)n dipeptide repeat that has been linked to amyotrophic lateral sclerosis (ALS) as a model of an arginine-rich CPP, we here show that the presence of (PR)n leads to a generalized displacement of RNA- and DNA-binding proteins from chromatin and mRNA. Accordingly, any reaction involving nucleic acids, such as RNA transcription, translation, splicing and degradation, or DNA replication and repair, is impaired by the presence of the CPPs. Interestingly, the effects of (PR)n are fully mimicked by protamine, a small arginine-rich protein that displaces histones from chromatin during spermatogenesis. We propose that widespread coating of nucleic acids and consequent displacement of RNA- and DNA-binding factors from chromatin and mRNA accounts for the toxicity of arginine-rich CPPs, including those that have been recently associated with the onset of ALS
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-07-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/711091
https://dx.doi.org/10.15252/embj.2019103311
url http://hdl.handle.net/10486/711091
https://dx.doi.org/10.15252/embj.2019103311
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv EMBO Press
publisher.none.fl_str_mv EMBO Press
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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