Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis

Subcellular compartmentalisation of metabolic enzymes may elicit specific cellular functions by establishing a unique metabolic environment. Indeed, the nuclear translocation of certain metabolic enzymes impacts epigenetics and gene expression regulation. In this thesis we reveal that, in cancer, th...

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Autor: Pardo Lorente, Natalia
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/689147
Acesso em linha:http://hdl.handle.net/10803/689147
Access Level:acceso abierto
Palavra-chave:Folate metabolism
Mitosis
Methylation
Centromere
Metabolic compartmentalisation
Metabolismo de los folatos
Metilación
Centrómero
Compartimentalización metabólica
575
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spelling Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosisPardo Lorente, NataliaFolate metabolismMitosisMethylationCentromereMetabolic compartmentalisationMetabolismo de los folatosMitosisMetilaciónCentrómeroCompartimentalización metabólica575Subcellular compartmentalisation of metabolic enzymes may elicit specific cellular functions by establishing a unique metabolic environment. Indeed, the nuclear translocation of certain metabolic enzymes impacts epigenetics and gene expression regulation. In this thesis we reveal that, in cancer, the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) localises in the nucleus during the G2-M phase of the cell cycle to secure mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability. Loss of MTHFD2 induces centromere overexpression and severe hypomethylation, leading to the accumulation of chromosomal aberrations arising from chromosome congression and segregation defects. Blocking the catalytic nuclear function of MTHFD2 recapitulates this phenotype, attributing to nuclear MTHFD2 an active role in controlling mitosis. Our discovery uncovers a nuclear moonlighting role for the cancer target MTHFD2, emphasising that the unconventional localisation of metabolic activities can impact the fate of mitosis.La compartimentalización subcelular de enzimas metabólicas puede desencadenar funciones celulares específicas estableciendo un entorno metabólico único. De hecho, la translocación nuclear de ciertas enzimas metabólicas afecta a la regulación epigenética y a la expresión génica. En esta tesis revelamos que, en cáncer, la enzima mitocondrial metilentetrahidrofolato deshidrogenasa 2 (MTHFD2) se localiza en el núcleo durante la fase G2-M del ciclo celular para garantizar la progresión de la mitosis. La MTHFD2 nuclear interacciona con proteínas involucradas en la regulación de la mitosis y la estabilidad de los centrómeros. La ausencia de MTHFD2 provoca la sobreexpresión de los centrómeros y su severa hipometilación, lo que conduce a la acumulación de alteraciones cromosómicas como consecuencia de defectos en la congresión y segregación de los cromosomas. El bloqueo de la función nuclear catalítica de MTHFD2 recapitula dicho fenotipo, atribuyendo a la MTHFD2 nuclear un rol activo en el control de la mitosis. Nuestro descubrimiento revela una función alternativa de la diana terapéutica del cáncer MTHFD2, y recalca que la localización no convencional de actividades metabólicas puede afectar al destino de la mitosis.Programa de Doctorat en BiomedicinaUniversitat Pompeu FabraSdelci, SaraUniversitat Pompeu Fabra. Departament de Medicina i Ciències de la Vida202320252023info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion180 p.application/pdfhttp://hdl.handle.net/10803/689147TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc/4.0/http://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6891472026-06-14T12:46:07Z
dc.title.none.fl_str_mv Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis
title Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis
spellingShingle Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis
Pardo Lorente, Natalia
Folate metabolism
Mitosis
Methylation
Centromere
Metabolic compartmentalisation
Metabolismo de los folatos
Mitosis
Metilación
Centrómero
Compartimentalización metabólica
575
title_short Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis
title_full Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis
title_fullStr Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis
title_full_unstemmed Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis
title_sort Deciphering the nuclear function of folate enzyme MTHFD2 in cancer: a novel role for nuclear MTHFD2 in mitosis
dc.creator.none.fl_str_mv Pardo Lorente, Natalia
author Pardo Lorente, Natalia
author_facet Pardo Lorente, Natalia
author_role author
dc.contributor.none.fl_str_mv Sdelci, Sara
Universitat Pompeu Fabra. Departament de Medicina i Ciències de la Vida
dc.subject.none.fl_str_mv Folate metabolism
Mitosis
Methylation
Centromere
Metabolic compartmentalisation
Metabolismo de los folatos
Mitosis
Metilación
Centrómero
Compartimentalización metabólica
575
topic Folate metabolism
Mitosis
Methylation
Centromere
Metabolic compartmentalisation
Metabolismo de los folatos
Mitosis
Metilación
Centrómero
Compartimentalización metabólica
575
description Subcellular compartmentalisation of metabolic enzymes may elicit specific cellular functions by establishing a unique metabolic environment. Indeed, the nuclear translocation of certain metabolic enzymes impacts epigenetics and gene expression regulation. In this thesis we reveal that, in cancer, the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) localises in the nucleus during the G2-M phase of the cell cycle to secure mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability. Loss of MTHFD2 induces centromere overexpression and severe hypomethylation, leading to the accumulation of chromosomal aberrations arising from chromosome congression and segregation defects. Blocking the catalytic nuclear function of MTHFD2 recapitulates this phenotype, attributing to nuclear MTHFD2 an active role in controlling mitosis. Our discovery uncovers a nuclear moonlighting role for the cancer target MTHFD2, emphasising that the unconventional localisation of metabolic activities can impact the fate of mitosis.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/689147
url http://hdl.handle.net/10803/689147
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 180 p.
application/pdf
dc.publisher.none.fl_str_mv Universitat Pompeu Fabra
publisher.none.fl_str_mv Universitat Pompeu Fabra
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425229754793984
score 15.301603

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