NASP modulates histone turnover to drive PARP inhibitor resistance

Sarah C. Moser, Anna Khalizieva, Josef Roehsner, Elisabeth Pottendorfer, Milo L. Kaptein, Giulia Ricci, Vivek Bhardwaj, Onno B. Bleijerveld, Liesbeth Hoekman, Ingrid Heijden, Simone Sanzo, Alexander Fish, Aleksandra Chikunova, Judith H. I. Haarhuis, Roel Oldenkamp, Luisa Robbez-Masson, Justin Sprengers, Daniel J. Vis, Lodewyk F. A. Wessels, Marieke Ven, Stephen J. Pettitt, Andrew N. J. Tutt, Christopher J. Lord, Benjamin D. Rowland, Moritz Völker-Albert, Francesca Mattiroli, Thijn R. Brummelkamp, Abdelghani Mazouzi () and Jos Jonkers ()
Additional contact information
Sarah C. Moser: Netherlands Cancer Institute
Anna Khalizieva: Netherlands Cancer Institute
Josef Roehsner: Netherlands Cancer Institute
Elisabeth Pottendorfer: Netherlands Cancer Institute
Milo L. Kaptein: Netherlands Cancer Institute
Giulia Ricci: Hubrecht Institute-KNAW and University Medical Center Utrecht
Vivek Bhardwaj: Utrecht University
Onno B. Bleijerveld: Netherlands Cancer Institute
Liesbeth Hoekman: Netherlands Cancer Institute
Ingrid Heijden: Netherlands Cancer Institute
Simone Sanzo: MOLEQLAR Analytics GmbH
Alexander Fish: Netherlands Cancer Institute
Aleksandra Chikunova: Netherlands Cancer Institute
Judith H. I. Haarhuis: Netherlands Cancer Institute
Roel Oldenkamp: Netherlands Cancer Institute
Luisa Robbez-Masson: The Institute of Cancer Research
Justin Sprengers: Netherlands Cancer Institute
Daniel J. Vis: Netherlands Cancer Institute
Lodewyk F. A. Wessels: Netherlands Cancer Institute
Marieke Ven: Netherlands Cancer Institute
Stephen J. Pettitt: The Institute of Cancer Research
Andrew N. J. Tutt: The Institute of Cancer Research
Christopher J. Lord: The Institute of Cancer Research
Benjamin D. Rowland: Netherlands Cancer Institute
Moritz Völker-Albert: MOLEQLAR Analytics GmbH
Francesca Mattiroli: Hubrecht Institute-KNAW and University Medical Center Utrecht
Thijn R. Brummelkamp: Oncode Institute
Abdelghani Mazouzi: Oncode Institute
Jos Jonkers: Netherlands Cancer Institute

Nature, 2025, vol. 645, issue 8082, 1071-1080

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09414-z

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