2. Academic Validation
  3. NASP modulates histone turnover to drive PARP inhibitor resistance

NASP modulates histone turnover to drive PARP inhibitor resistance

  • Nature. 2025 Aug 13. doi: 10.1038/s41586-025-09414-z.
Sarah C Moser 1 2,  Anna Khalizieva 1 2 3,  Josef Roehsner 1 2,  Elisabeth Pottendorfer 1 2,  Milo L Kaptein 1 2,  Giulia Ricci 4,  Vivek Bhardwaj 5,  Onno B Bleijerveld 6,  Liesbeth Hoekman 6,  Ingrid van der Heijden 1 2,  Simone di Sanzo 7,  Alexander Fish 8,  Aleksandra Chikunova 8,  Judith H I Haarhuis 9,  Roel Oldenkamp 9,  Luisa Robbez-Masson 10,  Justin Sprengers 11,  Daniel J Vis 12,  Lodewyk F A Wessels 12,  Marieke van de Ven 11,  Stephen J Pettitt 10,  Andrew N J Tutt 10 13,  Christopher J Lord 10,  Benjamin D Rowland 9,  Moritz Völker-Albert 7,  Francesca Mattiroli 4,  Thijn R Brummelkamp 2 8,  Abdelghani Mazouzi 14 15,  Jos Jonkers 16 17
Affiliations

Affiliations

  • 1 Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 2 Oncode Institute, Utrecht, Netherlands.
  • 3 Division of Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands.
  • 4 Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands.
  • 5 Institute of Biodynamics and Biocomplexity, Utrecht University, Utrecht, Netherlands.
  • 6 Mass Spectrometry/Proteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 7 MOLEQLAR Analytics GmbH, Munich, Germany.
  • 8 Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 9 Divison of Cell Biology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 10 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • 11 Mouse Clinic for Cancer and Aging Research, Intervention Unit, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 12 Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 13 The Breast Cancer Now Unit, Guy's Hospital, King's College London, London, UK.
  • 14 Oncode Institute, Utrecht, Netherlands. a.mazouzi@nki.nl.
  • 15 Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands. a.mazouzi@nki.nl.
  • 16 Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands. j.jonkers@nki.nl.
  • 17 Oncode Institute, Utrecht, Netherlands. j.jonkers@nki.nl.
PMID: 40804522 DOI: 10.1038/s41586-025-09414-z
Abstract

The poly(ADP-ribose) polymerase inhibitor (PARPi) class of drugs represents a remarkable advance in the treatment of patients with homologous recombination-deficient tumours, but resistance remains a challenge1-5. Although most research has focused on the downstream consequences of PARPi exposure to tackle resistance, the immediate effect of PARP inhibition on the chromatin environment and its contribution to PARPi toxicity remains elusive. Here we show that PARP inhibition induces histone release from the chromatin. This presents a vulnerability of PARPi-resistant Cancer cells, which require histone homeostasis mechanisms to sustain elevated DNA replication rates and survival. Through functional genetic screens, we identified NASP as a key factor in maintaining the stability of evicted histones via its TPR motifs. Loss of NASP renders tumour cells hypersensitive to PARPi treatment in vitro and in vivo, impairs replication fork progression and elevates levels of replication-associated DNA damage. Moreover, NASP acts together with the INO80 complex and the chaperoning activity of PARP1 to ensure efficient histone turnover and prevent the accumulation of lethal DNA damage. Collectively, our work reports on histone eviction as an immediate cellular response to PARPi treatment and provides a promising avenue for targeting histone supply pathways to overcome PARPi resistance.

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