2. Academic Validation
  3. Uracil processing by SMUG1 in the absence of UNG triggers homologous recombination and selectively kills BRCA1/2-deficient tumors

Uracil processing by SMUG1 in the absence of UNG triggers homologous recombination and selectively kills BRCA1/2-deficient tumors

  • Mol Cell. 2025 Mar 20;85(6):1072-1084.e10. doi: 10.1016/j.molcel.2025.01.031.
Daniele Musiani 1,  Hatice Yücel 1,  Marie Vallette 1,  Annapaola Angrisani 2,  Rania El Botty 3,  Bérengère Ouine 4,  Niccolo Schintu 1,  Caroline Adams 1,  Manon Chevalier 1,  Derrien Heloise 3,  Ahmed El Marjou 4,  Ivan Nemazanyy 5,  Marie Regairaz 6,  Elisabetta Marangoni 3,  Daniele Fachinetti 2,  Raphael Ceccaldi 7
Affiliations

Affiliations

  • 1 INSERM U830, PSL Research University, Institut Curie, Paris, France.
  • 2 Institut Curie, PSL Research University, Sorbonne Université, CNRS, UMR144 and UMR3664, 26 rue d'Ulm, 75005 Paris, France.
  • 3 Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France.
  • 4 Recombinant Protein Facility CNRS UMR144, Institut Curie, PSL Research University, Paris, France.
  • 5 Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR 3633, Paris, France.
  • 6 INSERM U830, PSL Research University, Institut Curie, Paris, France; Laboratoire de Biologie et Pharmacologie Appliquée, ENS-Paris-Saclay, CNRS UMR 8113, Université Paris-Saclay, 91190 Gif-sur-Yvette, France.
  • 7 INSERM U830, PSL Research University, Institut Curie, Paris, France. Electronic address: raphael.ceccaldi@curie.fr.
PMID: 40010343 DOI: 10.1016/j.molcel.2025.01.031
Abstract

Resistance to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) is the major obstacle to their effectiveness in the treatment of homologous recombination (HR)-deficient (HRD) tumors. Hence, developing alternative treatments for HRD tumors is critical. Here, we show that targeting the uracil excision pathway kills HRD tumors, including those with PARPi resistance. We found that the interplay between the two major uracil DNA glycosylases UNG and SMUG1 is regulated by nuclear nicotinamide adenine dinucleotide (NAD+), which maintains UNG at replication forks (RFs) and restrains SMUG1 chromatin binding. In the absence of UNG, SMUG1 retention on chromatin leads to persistent abasic sites, which incision by APE1 results in PARP1 hyperactivation, stalled RFs, and RAD51 foci. In HRD cells (i.e., BRCA1/2-deficient), this leads to under-replicated DNA that, when propagated throughout mitosis, results in chromosome fragmentation and cell death. Our findings open up unique possibilities for targeted therapies for HRD tumors based on UNG inhibition and uracil accumulation in the genome.

Keywords

HR-deficient breast and ovarian tumors; PARP1 hyperactivation; PARPi resistance; SMUG1/UNG crosstalk; dUTP DNA incorporation; genomic instability; nuclear NAD(+); replication stress; synthetic lethality; uracil excision repair.

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