Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain

Autores
Bedez, Claire; Lotz, Christophe; Batisse, Claire; Broeck, Arnaud Vanden; Stote, Roland H.; Howard, Eduardo Ignacio; Pradeau Aubreton, Karine; Ruff, Marc; Lamour, Valérie
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Type 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems. Structural analysis revealed that acetylation sites are clustered on the catalytic domains of the homodimer while phosphorylation sites are located in the C-terminal domain responsible for nuclear localization. Biochemical analysis of the eukaryotic-specific K168 residue in the ATPase domain shows that acetylation affects a key position regulating ATP hydrolysis through the modulation of dimerization. Our findings suggest that acetylation of specific sites involved in the allosteric regulation of human Top2 may provide a mechanism for modulation of its catalytic activity.
Facultad de Ciencias Exactas
Instituto de Física de Líquidos y Sistemas Biológicos
Materia
Ciencias Exactas
Física
Biología
DNA topoisomerase 2α
Post-translational modifications
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by/4.0/
Repositorio
SEDICI (UNLP)
Institución
Universidad Nacional de La Plata
OAI Identificador
oai:sedici.unlp.edu.ar:10915/100487
Acceder
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oai_identifier_str oai:sedici.unlp.edu.ar:10915/100487
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repository_id_str 1329
network_name_str SEDICI (UNLP)
spelling Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domainBedez, ClaireLotz, ChristopheBatisse, ClaireBroeck, Arnaud VandenStote, Roland H.Howard, Eduardo IgnacioPradeau Aubreton, KarineRuff, MarcLamour, ValérieCiencias ExactasFísicaBiologíaDNA topoisomerase 2αPost-translational modificationsType 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems. Structural analysis revealed that acetylation sites are clustered on the catalytic domains of the homodimer while phosphorylation sites are located in the C-terminal domain responsible for nuclear localization. Biochemical analysis of the eukaryotic-specific K168 residue in the ATPase domain shows that acetylation affects a key position regulating ATP hydrolysis through the modulation of dimerization. Our findings suggest that acetylation of specific sites involved in the allosteric regulation of human Top2 may provide a mechanism for modulation of its catalytic activity.Facultad de Ciencias ExactasInstituto de Física de Líquidos y Sistemas Biológicos2018-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://sedici.unlp.edu.ar/handle/10915/100487enginfo:eu-repo/semantics/altIdentifier/url/https://ri.conicet.gov.ar/11336/89288info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/s41598-018-27606-8info:eu-repo/semantics/altIdentifier/issn/2045-2322info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-018-27606-8info:eu-repo/semantics/altIdentifier/hdl/11336/89288info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International (CC BY 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2025-10-15T11:12:28Zoai:sedici.unlp.edu.ar:10915/100487Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292025-10-15 11:12:29.147SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain
title Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain
spellingShingle Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain
Bedez, Claire
Ciencias Exactas
Física
Biología
DNA topoisomerase 2α
Post-translational modifications
title_short Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain
title_full Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain
title_fullStr Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain
title_full_unstemmed Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain
title_sort Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain
dc.creator.none.fl_str_mv Bedez, Claire
Lotz, Christophe
Batisse, Claire
Broeck, Arnaud Vanden
Stote, Roland H.
Howard, Eduardo Ignacio
Pradeau Aubreton, Karine
Ruff, Marc
Lamour, Valérie
author Bedez, Claire
author_facet Bedez, Claire
Lotz, Christophe
Batisse, Claire
Broeck, Arnaud Vanden
Stote, Roland H.
Howard, Eduardo Ignacio
Pradeau Aubreton, Karine
Ruff, Marc
Lamour, Valérie
author_role author
author2 Lotz, Christophe
Batisse, Claire
Broeck, Arnaud Vanden
Stote, Roland H.
Howard, Eduardo Ignacio
Pradeau Aubreton, Karine
Ruff, Marc
Lamour, Valérie
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ciencias Exactas
Física
Biología
DNA topoisomerase 2α
Post-translational modifications
topic Ciencias Exactas
Física
Biología
DNA topoisomerase 2α
Post-translational modifications
dc.description.none.fl_txt_mv Type 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems. Structural analysis revealed that acetylation sites are clustered on the catalytic domains of the homodimer while phosphorylation sites are located in the C-terminal domain responsible for nuclear localization. Biochemical analysis of the eukaryotic-specific K168 residue in the ATPase domain shows that acetylation affects a key position regulating ATP hydrolysis through the modulation of dimerization. Our findings suggest that acetylation of specific sites involved in the allosteric regulation of human Top2 may provide a mechanism for modulation of its catalytic activity.
Facultad de Ciencias Exactas
Instituto de Física de Líquidos y Sistemas Biológicos
description Type 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems. Structural analysis revealed that acetylation sites are clustered on the catalytic domains of the homodimer while phosphorylation sites are located in the C-terminal domain responsible for nuclear localization. Biochemical analysis of the eukaryotic-specific K168 residue in the ATPase domain shows that acetylation affects a key position regulating ATP hydrolysis through the modulation of dimerization. Our findings suggest that acetylation of specific sites involved in the allosteric regulation of human Top2 may provide a mechanism for modulation of its catalytic activity.
publishDate 2018
dc.date.none.fl_str_mv 2018-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Articulo
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://sedici.unlp.edu.ar/handle/10915/100487
url http://sedici.unlp.edu.ar/handle/10915/100487
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://ri.conicet.gov.ar/11336/89288
info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/s41598-018-27606-8
info:eu-repo/semantics/altIdentifier/issn/2045-2322
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-018-27606-8
info:eu-repo/semantics/altIdentifier/hdl/11336/89288
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
Creative Commons Attribution 4.0 International (CC BY 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
Creative Commons Attribution 4.0 International (CC BY 4.0)
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:SEDICI (UNLP)
instname:Universidad Nacional de La Plata
instacron:UNLP
reponame_str SEDICI (UNLP)
collection SEDICI (UNLP)
instname_str Universidad Nacional de La Plata
instacron_str UNLP
institution UNLP
repository.name.fl_str_mv SEDICI (UNLP) - Universidad Nacional de La Plata
repository.mail.fl_str_mv alira@sedici.unlp.edu.ar
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score 13.22299

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