Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

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 Bantulà, Laura Pascual-Reguant, Evangelia Darai, Maria Guirola, Joan Montero and Sara Sdelci ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53877-z

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