Espinar, LorenaGarcia-Cao, MartaSchmidt, AlisaKourtis, SavvasGañez-Zapater, AntoniAranda Vallejo, CarlaGhose, RitobrataGarcía-López, LauraSheraj, IlirPardo Lorente, NataliaBantulà, MarinaPascual-Reguant, LauraDarai, EvangeliaGuirola, MariaMontero, JoanSdelci, Sara2025-01-312025-01-312024Espinar 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-z2041-1723http://hdl.handle.net/10230/69403Nuclear 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-024-53877-zBreast cancerCancer metabolismDNA damage and repairinfo:eu-repo/semantics/openAccess