A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability

While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrat...

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Autores: Moretton, Amandine, Kourtis, Savvas, Gañez-Zapater, Antoni, Calabrò, Chiara, Espinar Calvo, Maria Lorena, Fontaine, Frédéric, Darai, Evangelia, Abad Cortel, Etna, Block, Samuel, Pascual-Reguant, Laura, 1990-, Pardo-Lorente, Natalia, Ghose, Ritobrata, Vander Heiden, Matthew G., Janic, Ana, Müller, André C., Loizou, Joanna I., Sdelci, Sara
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/57559
Acceso en línea:http://hdl.handle.net/10230/57559
http://dx.doi.org/10.15252/msb.202211267
Access Level:acceso abierto
Palabra clave:DNA damage response
Peroxiredoxin 1
Aspartate metabolism
Electron transport chain
Reactive oxygen species scavenging
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spelling A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availabilityMoretton, AmandineKourtis, SavvasGañez-Zapater, AntoniCalabrò, ChiaraEspinar Calvo, Maria LorenaFontaine, FrédéricDarai, EvangeliaAbad Cortel, EtnaBlock, SamuelPascual-Reguant, Laura, 1990-Pardo-Lorente, NataliaGhose, RitobrataVander Heiden, Matthew G.Janic, AnaMüller, André C.Loizou, Joanna I.Sdelci, SaraDNA damage responsePeroxiredoxin 1Aspartate metabolismElectron transport chainReactive oxygen species scavengingWhile cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.AM and CC were funded by the Austrian Science Fund (grant number P 33024 awarded to JIL). The Loizou lab is funded by an ERC Synergy Grant (DDREAMM Grant agreement ID: 855741). The Sdelci lab's contributions to this study were funded by an ERC Starting Grant (ERC-StG-852343-EPICAMENTE). This work was funded, in part, by a donation from Benjamin Landesmann. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. CeMM is funded by the Austrian Academy of Sciences. MGVH acknowledges funding from R35CA242379, the Lustgarten Foundation, the Ludwig Center at MIT, and the MIT Center for Precision Cancer Medicine.EMBO Press202320232023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/57559http://dx.doi.org/10.15252/msb.202211267reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésMol Syst Biol. 2023 Jul 11;19(7):e11267info:eu-repo/grantAgreement/EC/H2020/855741info:eu-repo/grantAgreement/EC/H2020/852343© 2023 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/575592026-06-12T07:21:37Z
dc.title.none.fl_str_mv A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability
title A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability
spellingShingle A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability
Moretton, Amandine
DNA damage response
Peroxiredoxin 1
Aspartate metabolism
Electron transport chain
Reactive oxygen species scavenging
title_short A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability
title_full A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability
title_fullStr A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability
title_full_unstemmed A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability
title_sort A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability
dc.creator.none.fl_str_mv Moretton, Amandine
Kourtis, Savvas
Gañez-Zapater, Antoni
Calabrò, Chiara
Espinar Calvo, Maria Lorena
Fontaine, Frédéric
Darai, Evangelia
Abad Cortel, Etna
Block, Samuel
Pascual-Reguant, Laura, 1990-
Pardo-Lorente, Natalia
Ghose, Ritobrata
Vander Heiden, Matthew G.
Janic, Ana
Müller, André C.
Loizou, Joanna I.
Sdelci, Sara
author Moretton, Amandine
author_facet Moretton, Amandine
Kourtis, Savvas
Gañez-Zapater, Antoni
Calabrò, Chiara
Espinar Calvo, Maria Lorena
Fontaine, Frédéric
Darai, Evangelia
Abad Cortel, Etna
Block, Samuel
Pascual-Reguant, Laura, 1990-
Pardo-Lorente, Natalia
Ghose, Ritobrata
Vander Heiden, Matthew G.
Janic, Ana
Müller, André C.
Loizou, Joanna I.
Sdelci, Sara
author_role author
author2 Kourtis, Savvas
Gañez-Zapater, Antoni
Calabrò, Chiara
Espinar Calvo, Maria Lorena
Fontaine, Frédéric
Darai, Evangelia
Abad Cortel, Etna
Block, Samuel
Pascual-Reguant, Laura, 1990-
Pardo-Lorente, Natalia
Ghose, Ritobrata
Vander Heiden, Matthew G.
Janic, Ana
Müller, André C.
Loizou, Joanna I.
Sdelci, Sara
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv DNA damage response
Peroxiredoxin 1
Aspartate metabolism
Electron transport chain
Reactive oxygen species scavenging
topic DNA damage response
Peroxiredoxin 1
Aspartate metabolism
Electron transport chain
Reactive oxygen species scavenging
description While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/57559
http://dx.doi.org/10.15252/msb.202211267
url http://hdl.handle.net/10230/57559
http://dx.doi.org/10.15252/msb.202211267
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Mol Syst Biol. 2023 Jul 11;19(7):e11267
info:eu-repo/grantAgreement/EC/H2020/855741
info:eu-repo/grantAgreement/EC/H2020/852343
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv EMBO Press
publisher.none.fl_str_mv EMBO Press
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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