Nucleophosmin interaction with APE1: Insights into DNA repair regulation

[EN] Nucleophosmin (NPM1), an abundant, nucleolar protein with multiple functions affecting cell homeostasis, has also been recently involved in DNA damage repair. The roles of NPM1 in different repair pathways remain however to be elucidated. NPM1 has been described to interact with APE1 (apurinic...

Descripción completa

Detalles Bibliográficos
Autores: López Jiménez, David, De Blas Martín, Ander, Hurtado, Mikel, García Alija, Mike, Mentxaka Salgado, Jon, De la Arada Echevarría, Igor, Urbaneja Arrue, María Ángeles, Alonso Mariño, Marian, Bañuelos Rodríguez, Sonia
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/66677
Acceso en línea:http://hdl.handle.net/10810/66677
Access Level:acceso abierto
Palabra clave:APE1
NPM1
nucleophosmin
BER Base excision repair
protein-protein interaction
id ES_721cfedd02f2197de1c4c8dd4d82019f
oai_identifier_str oai:addi.ehu.eus:10810/66677
network_acronym_str ES
network_name_str España
repository_id_str
spelling Nucleophosmin interaction with APE1: Insights into DNA repair regulationLópez Jiménez, DavidDe Blas Martín, AnderHurtado, MikelGarcía Alija, MikeMentxaka Salgado, JonDe la Arada Echevarría, IgorUrbaneja Arrue, María ÁngelesAlonso Mariño, MarianBañuelos Rodríguez, SoniaAPE1NPM1nucleophosminBER Base excision repairprotein-protein interaction[EN] Nucleophosmin (NPM1), an abundant, nucleolar protein with multiple functions affecting cell homeostasis, has also been recently involved in DNA damage repair. The roles of NPM1 in different repair pathways remain however to be elucidated. NPM1 has been described to interact with APE1 (apurinic apyrimidinic endonuclease 1), a key enzyme of the base excision repair (BER) pathway, which could reflect a direct participation of NPM1 in this route. To gain insight into the possible role(s) of NPM1 in BER, we have explored the interplay between the subnuclear localization of both APE1 and NPM1, the in vitro interaction they establish, the effect of binding to abasic DNA on APE1 conformation, and the modulation by NPM1 of APE1 binding and catalysis on DNA. We have found that, upon oxidative damage, NPM1 is released from nucleoli and locates on patches throughout the chromatin, perhaps co-localizing with APE1, and that this traffic could be mediated by phosphorylation of NPM1 on T199. NPM1 and APE1 form a complex in vitro, involving, apart from the core domain, at least part of the linker region of NPM1, whereas the C-terminal domain is dispensable for binding, which explains that an AML leukemia-related NPM1 mutant with an unfolded C-terminal domain can bind APE1. APE1 interaction with abasic DNA stabilizes APE1 structure, as based on thermal unfolding. Moreover, our data suggest that NPM1, maybe by keeping APE1 in an "open" conformation, favours specific recognition of abasic sites on DNA, competing with off-target associations. Therefore, NPM1 might participate in BER favouring APE1 target selection as well as turnover from incised abasic DNA.The authors thank the staff from the High Resolution Microscopy Facility (SGIker-UPV/EHU) for technical support, Dr. José Martínez (University of Granada) for advice on interpretation of ITC data, and Dr. José Antonio Rodríguez (University of the Basque Country) for suggestions and advice. A.dB. and M.G. were recipients of an Ikasiker fellowship (Basque Government).Elsevier202420242020info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/66677reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttps://www.sciencedirect.com/science/article/pii/S1568786419303210?via%3Dihub#ack0005info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/© 2020 Elsevier under CC BY-NC-ND licenseoai:addi.ehu.eus:10810/666772026-06-18T09:23:17Z
dc.title.none.fl_str_mv Nucleophosmin interaction with APE1: Insights into DNA repair regulation
title Nucleophosmin interaction with APE1: Insights into DNA repair regulation
spellingShingle Nucleophosmin interaction with APE1: Insights into DNA repair regulation
López Jiménez, David
APE1
NPM1
nucleophosmin
BER Base excision repair
protein-protein interaction
title_short Nucleophosmin interaction with APE1: Insights into DNA repair regulation
title_full Nucleophosmin interaction with APE1: Insights into DNA repair regulation
title_fullStr Nucleophosmin interaction with APE1: Insights into DNA repair regulation
title_full_unstemmed Nucleophosmin interaction with APE1: Insights into DNA repair regulation
title_sort Nucleophosmin interaction with APE1: Insights into DNA repair regulation
dc.creator.none.fl_str_mv López Jiménez, David
De Blas Martín, Ander
Hurtado, Mikel
García Alija, Mike
Mentxaka Salgado, Jon
De la Arada Echevarría, Igor
Urbaneja Arrue, María Ángeles
Alonso Mariño, Marian
Bañuelos Rodríguez, Sonia
author López Jiménez, David
author_facet López Jiménez, David
De Blas Martín, Ander
Hurtado, Mikel
García Alija, Mike
Mentxaka Salgado, Jon
De la Arada Echevarría, Igor
Urbaneja Arrue, María Ángeles
Alonso Mariño, Marian
Bañuelos Rodríguez, Sonia
author_role author
author2 De Blas Martín, Ander
Hurtado, Mikel
García Alija, Mike
Mentxaka Salgado, Jon
De la Arada Echevarría, Igor
Urbaneja Arrue, María Ángeles
Alonso Mariño, Marian
Bañuelos Rodríguez, Sonia
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv APE1
NPM1
nucleophosmin
BER Base excision repair
protein-protein interaction
topic APE1
NPM1
nucleophosmin
BER Base excision repair
protein-protein interaction
description [EN] Nucleophosmin (NPM1), an abundant, nucleolar protein with multiple functions affecting cell homeostasis, has also been recently involved in DNA damage repair. The roles of NPM1 in different repair pathways remain however to be elucidated. NPM1 has been described to interact with APE1 (apurinic apyrimidinic endonuclease 1), a key enzyme of the base excision repair (BER) pathway, which could reflect a direct participation of NPM1 in this route. To gain insight into the possible role(s) of NPM1 in BER, we have explored the interplay between the subnuclear localization of both APE1 and NPM1, the in vitro interaction they establish, the effect of binding to abasic DNA on APE1 conformation, and the modulation by NPM1 of APE1 binding and catalysis on DNA. We have found that, upon oxidative damage, NPM1 is released from nucleoli and locates on patches throughout the chromatin, perhaps co-localizing with APE1, and that this traffic could be mediated by phosphorylation of NPM1 on T199. NPM1 and APE1 form a complex in vitro, involving, apart from the core domain, at least part of the linker region of NPM1, whereas the C-terminal domain is dispensable for binding, which explains that an AML leukemia-related NPM1 mutant with an unfolded C-terminal domain can bind APE1. APE1 interaction with abasic DNA stabilizes APE1 structure, as based on thermal unfolding. Moreover, our data suggest that NPM1, maybe by keeping APE1 in an "open" conformation, favours specific recognition of abasic sites on DNA, competing with off-target associations. Therefore, NPM1 might participate in BER favouring APE1 target selection as well as turnover from incised abasic DNA.
publishDate 2020
dc.date.none.fl_str_mv 2020
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/66677
url http://hdl.handle.net/10810/66677
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://www.sciencedirect.com/science/article/pii/S1568786419303210?via%3Dihub#ack0005
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
© 2020 Elsevier under CC BY-NC-ND license
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
© 2020 Elsevier under CC BY-NC-ND license
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869410700775915520
score 15,301603

Similares en LA Referencia