Nuclear localization of MTHFD2 is required for correct mitosis progression

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  • dc.contributor.author Pardo Lorente, Natalia
  • dc.contributor.author Gkanogiannis, Anestis
  • dc.contributor.author Cozzuto, Luca
  • dc.contributor.author Gañez-Zapater, Antoni
  • dc.contributor.author Espinar, Lorena
  • dc.contributor.author Ghose, Ritobrata
  • dc.contributor.author Severino, Jacqueline, 1990-
  • dc.contributor.author García-López, Laura
  • dc.contributor.author Aydin, Rabia Gül
  • dc.contributor.author Martin, Laura
  • dc.contributor.author Neguembor, Maria Victoria
  • dc.contributor.author Darai, Evangelia
  • dc.contributor.author Cosma, Maria Pia
  • dc.contributor.author Batlle Morera, Laura
  • dc.contributor.author Ponomarenko, Julia
  • dc.contributor.author Sdelci, Sara
  • dc.date.accessioned 2025-01-31T07:54:53Z
  • dc.date.available 2025-01-31T07:54:53Z
  • dc.date.issued 2024
  • dc.description.abstract Subcellular compartmentalization of metabolic enzymes establishes a unique metabolic environment that elicits specific cellular functions. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we show that the nuclear localization of the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) ensures mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces severe methylation defects and impedes correct mitosis completion. MTHFD2 deficient cells display chromosome congression and segregation defects and accumulate chromosomal aberrations. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, whereas restricting MTHFD2 to the nucleus is sufficient to ensure correct mitotic progression. Our discovery uncovers a nuclear role for MTHFD2, supporting the notion that translocation of metabolic enzymes to the nucleus is required to meet precise chromatin needs.
  • dc.description.sponsorship We acknowledge support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI /10.13039/501100011033), and the Generalitat de Catalunya through the CERCA programme. We are grateful to the CRG Core Technologies Programme for their support and assistance in this work. We would like to thank the CRG and CNAG Sequencing Facilities (Barcelona, Spain) for all next-generation sequencing, the CRG Proteomics Facility (Barcelona, Spain) for the MTHFD2 interactome analysis, the CRG Flow Cytometry Facility (Barcelona, Spain) for the sorting, the IMIM Platform for molecular cytogenetics (Barcelona, Spain) for the karyotype analysis, and MARbiobank for provision of patient samples for organoid generation. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech). We would like to thank Prof. Thomas Helleday for providing the MTHFD2 inhibitor TH9619 and for the fruitful discussions. N.P.L. was supported by a Boehringer Ingelheim Fonds Ph.D. fellowship. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 852343, ERC-StG-852343-EPICAMENTE) and from a Spanish Plan Estatal grant (Ministerio de Ciencia e Innovación, Project PID2019-110598GA-I00 funded by MICIU/AEI /10.13039/501100011033).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Pardo-Lorente N, Gkanogiannis A, Cozzuto L, Gañez Zapater A, Espinar L, Ghose R, et al. Nuclear localization of MTHFD2 is required for correct mitosis progression. Nat Commun. 2024 Nov 12;15(1):9529. DOI: 10.1038/s41467-024-51847-z
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-51847-z
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/69404
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2024 Nov 12;15(1):9529
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/852343
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-110598GA-I00
  • dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword Epigenetics
  • dc.subject.keyword Histone post-translational modifications
  • dc.subject.keyword Mitosis
  • dc.title Nuclear localization of MTHFD2 is required for correct mitosis progression
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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