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. 2025 Sep;645(8082):1071-1080.
doi: 10.1038/s41586-025-09414-z. Epub 2025 Aug 13.

NASP modulates histone turnover to drive PARP inhibitor resistance

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

NASP modulates histone turnover to drive PARP inhibitor resistance

Sarah C Moser et al. Nature. 2025 Sep.

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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Conflict of interest statement

Competing interests: M.V.-A. is a shareholder of MoleQlar Analytics. T.R.B. is a co-founder and shareholder of Scenic Biotech B.V. J.J. has received research funding from Artios Pharma. C.J.L. receives and/or has received research funding from AstraZeneca, Merck KGaA, Artios, Neophore and FoRx; received consultancy, SAB membership or honoraria payments from FoRx, Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango Therapeutics, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics, Pontifax, Astex, Neophore, GlaxoSmithKline, Dawn Bioventures, Blacksmith Medicines, ForEx and Ariceum; and has stock in Tango, Ovibio, Hysplex, Tesselate and Ariceum. A.N.J.T. is or has been a consultant for AstraZeneca, Merck KGaA, Artios, Pfizer, Vertex, Gilead and MD Anderson Cancer Centre; and has received grant and/or research support from AstraZeneca, Myriad and Merck KgaA. C.J.L. and A.N.J.T. are named inventors on patents describing the use of DNA repair inhibitors and stand to gain from their development and use as part of the ICR ‘Rewards to Inventors’ scheme and also report benefits from this scheme associated with patents for PARP inhibitors paid to the research accounts for C.J.L. and A.N.J.T. at the Institute of Cancer Research. All other authors declare no competing interests.

References

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