2. Academic Validation
  3. Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

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.
Lorena Espinar # 1,  Marta Garcia-Cao # 2,  Alisa Schmidt 1,  Savvas Kourtis 1,  Antoni Gañez Zapater 1,  Carla Aranda-Vallejo 1,  Ritobrata Ghose 1,  Laura Garcia-Lopez 1,  Ilir Sheraj 1,  Natalia Pardo-Lorente 1,  Marina Bantulà 3,  Laura Pascual-Reguant 1,  Evangelia Darai 1,  Maria Guirola 1,  Joan Montero 3,  Sara Sdelci 4 5
Affiliations

Affiliations

  • 1 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain.
  • 2 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain. marta.garciacao@crg.eu.
  • 3 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain.
  • 4 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain. sara.sdelci@crg.eu.
  • 5 Universitat Pompeu Fabra (UPF), Barcelona, Spain. sara.sdelci@crg.eu.
  • # Contributed equally.
PMID: 39532854 DOI: 10.1038/s41467-024-53877-z
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.

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