Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Espinar, Lorena; Garcia-Cao, Marta; Schmidt, Alisa; Kourtis, Savvas; Gañez-Zapater, Antoni; Aranda Vallejo, Carla; Ghose, Ritobrata; García-López, Laura; Sheraj, Ilir; Pardo Lorente, Natalia; Bantulà, Marina; Pascual-Reguant, Laura; Darai, Evangelia; Guirola, Maria; Montero, Joan; Sdelci, Sara

Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

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dc.contributor.author Espinar, Lorena
dc.contributor.author Garcia-Cao, Marta
dc.contributor.author Schmidt, Alisa
dc.contributor.author Kourtis, Savvas
dc.contributor.author Gañez-Zapater, Antoni
dc.contributor.author Aranda Vallejo, Carla
dc.contributor.author Ghose, Ritobrata
dc.contributor.author García-López, Laura
dc.contributor.author Sheraj, Ilir
dc.contributor.author Pardo Lorente, Natalia
dc.contributor.author Bantulà, Marina
dc.contributor.author Pascual-Reguant, Laura
dc.contributor.author Darai, Evangelia
dc.contributor.author Guirola, Maria
dc.contributor.author Montero, Joan
dc.contributor.author Sdelci, Sara
dc.date.accessioned 2025-01-31T07:54:32Z
dc.date.available 2025-01-31T07:54:32Z
dc.date.issued 2024
dc.description.abstract Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular links remain elusive. Here, we explore this crosstalk using triple-negative breast cancer (TNBC) as a model, a subtype often prone to DNA damage accumulation. We show that the de novo purine synthesis enzyme IMPDH2 is enriched on chromatin in TNBC compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent, and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts with and modulates PARP1 activity by controlling the nuclear availability of NAD+ to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2, acting as a convergence point of nuclear metabolism and DNA damage response.
dc.description.sponsorship The authors would like to thank the Genomics Unit at the CRG for assistance with the sequencing, the CRG Proteomics Facility (Barcelona, Spain) for the chromatome MS analysis, the CRG Flow Cytometry Facility (Barcelona, Spain) for the cell cycle analysis, Dr. Ivan Perez-Nuñez from Dr. Toni Celià-Terrassa group (IMIM, Barcelona, Spain) for helping with the IHC analysis. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech). We acknowledge the 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 program. N.P.L. is supported by a Boehringer Ingelheim Fonds Ph.D. fellowship. L.P.R. is supported by a Fundación Francisco Cobo (Eduardo Gallego) postdoctoral fellowship. The Sdelci lab’s contributions to this study have received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 852343), and from the Spanish Plan Estatal grants (Ministerio de Ciencia e Innovación, PID2019-110598GA-I00/AEI/10.13039/501100011033 and PID2022-141740NB-I00 funded by MICIU /AEI /10.13039/501100011033 / FEDER, UE) and from Fundación BBVA under Beca Leonardo a Investigadores y Creadores Culturales 2022 (LEO22-2-2290-BBM-BAS-167).
dc.format.mimetype application/pdf
dc.identifier.citation Espinar L, Garcia-Cao M, Schmidt A, Kourtis S, Gañez Zapater A, Aranda-Vallejo C, et al. Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity. Nat Commun. 2024 Nov 12;15(1):9515. DOI: 10.1038/s41467-024-53877-z
dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-53877-z
dc.identifier.issn 2041-1723
dc.identifier.uri http://hdl.handle.net/10230/69403
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nat Commun. 2024 Nov 12;15(1):9515
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/852343
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-110598GA-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-141740NB-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 Breast cancer
dc.subject.keyword Cancer metabolism
dc.subject.keyword DNA damage and repair
dc.title Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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