NASP modulates histone turnover to drive PARP inhibitor resistance

• 成果类型: Article
• 署名作者: Moser, Sarah C.; Khalizieva, Anna; Roehsner, Josef; Pottendorfer, Elisabeth; Kaptein, Milo L.; Ricci, Giulia; Bhardwaj, Vivek; Bleijerveld, Onno B.; Hoekman, Liesbeth; van der Heijden, Ingrid; di Sanzo, Simone; Fish, Alexander; Chikunova, Aleksandra; Haarhuis, Judith H. I.; Oldenkamp, Roel; Robbez-Masson, Luisa; Sprengers, Justin; Vis, Daniel J.; Wessels, Lodewyk F. A.; van de Ven, Marieke; Pettitt, Stephen J.; Tutt, Andrew N. J.; Lord, Christopher J.; Rowland, Benjamin D.; Voelker-Albert, Moritz; Mattiroli, Francesca; Brummelkamp, Thijn R.; Mazouzi, Abdelghani; Jonkers, Jos
• 署名单位: Netherlands Cancer Institute; Leiden University - Excl LUMC; Leiden University; Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center; Utrecht University; Netherlands Cancer Institute; Netherlands Cancer Institute; Netherlands Cancer Institute; University of London; Royal Marsden NHS Foundation Trust; Institute of Cancer Research - UK; Netherlands Cancer Institute; Netherlands Cancer Institute; Guy's & St Thomas' NHS Foundation Trust; University of London; King's College London
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09414-z
• 发表日期: 2025-09-25
• 关键词: homologous-recombination; ovarian-cancer; maintenance therapy; synthetic lethality; dna-repair; chromatin; protein; cells; ubiquitylation; DYNAMICS

摘要

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, 2, 3, 4-5. 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.