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Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Author

Listed:
  • Lorena Espinar

    (Dr. Aiguader 88)

  • Marta Garcia-Cao

    (Dr. Aiguader 88)

  • Alisa Schmidt

    (Dr. Aiguader 88)

  • Savvas Kourtis

    (Dr. Aiguader 88)

  • Antoni Gañez Zapater

    (Dr. Aiguader 88)

  • Carla Aranda-Vallejo

    (Dr. Aiguader 88)

  • Ritobrata Ghose

    (Dr. Aiguader 88)

  • Laura Garcia-Lopez

    (Dr. Aiguader 88)

  • Ilir Sheraj

    (Dr. Aiguader 88)

  • Natalia Pardo-Lorente

    (Dr. Aiguader 88)

  • Marina Bantulà

    (Universitat de Barcelona)

  • Laura Pascual-Reguant

    (Dr. Aiguader 88)

  • Evangelia Darai

    (Dr. Aiguader 88)

  • Maria Guirola

    (Dr. Aiguader 88)

  • Joan Montero

    (Universitat de Barcelona)

  • Sara Sdelci

    (Dr. Aiguader 88
    Universitat Pompeu Fabra (UPF))

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.

Suggested Citation

  • Lorena Espinar & Marta Garcia-Cao & Alisa Schmidt & Savvas Kourtis & Antoni Gañez Zapater & Carla Aranda-Vallejo & Ritobrata Ghose & Laura Garcia-Lopez & Ilir Sheraj & Natalia Pardo-Lorente & Marina B, 2024. "Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53877-z
    DOI: 10.1038/s41467-024-53877-z
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    References listed on IDEAS

    as
    1. Neha Chopra & Holly Tovey & Alex Pearson & Ros Cutts & Christy Toms & Paula Proszek & Michael Hubank & Mitch Dowsett & Andrew Dodson & Frances Daley & Divya Kriplani & Heidi Gevensleben & Helen Ruth D, 2020. "Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. Donna R Whelan & Wei Ting C Lee & Frances Marks & Yu Tina Kong & Yandong Yin & Eli Rothenberg, 2020. "Super-resolution visualization of distinct stalled and broken replication fork structures," PLOS Genetics, Public Library of Science, vol. 16(12), pages 1-28, December.
    3. Luke A. Yates & Ricardo J. Aramayo & Nilisha Pokhrel & Colleen C. Caldwell & Joshua A. Kaplan & Rajika L. Perera & Maria Spies & Edwin Antony & Xiaodong Zhang, 2018. "A structural and dynamic model for the assembly of Replication Protein A on single-stranded DNA," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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