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, Völker-Albert Moritz, Mattiroli Francesca, Brummelkamp Thijn R, Mazouzi Abdelghani, Jonkers Jos
Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
Oncode Institute, Utrecht, Netherlands.
Nature. 2025 Aug 13. doi: 10.1038/s41586-025-09414-z.
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 challenge. 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.
聚（ADP - 核糖）聚合酶抑制剂（PARPi）类药物在治疗同源重组缺陷肿瘤患者方面取得了显著进展，但耐药性仍然是一个挑战。尽管大多数研究集中在PARPi暴露的下游后果以应对耐药性，但PARP抑制对染色质环境的直接影响及其对PARPi毒性的作用仍不清楚。在这里，我们表明PARP抑制会诱导组蛋白从染色质中释放。这揭示了PARPi耐药癌细胞的一个弱点，这些细胞需要组蛋白稳态机制来维持较高的DNA复制速率和存活率。通过功能基因筛选，我们确定NASP是通过其TPR基序维持被驱逐组蛋白稳定性的关键因素。NASP的缺失使肿瘤细胞在体外和体内对PARPi治疗高度敏感，损害复制叉进展并提高复制相关DNA损伤水平。此外，NASP与INO80复合物以及PARP1的伴侣活性共同作用，以确保有效的组蛋白周转并防止致命DNA损伤的积累。总体而言，我们的工作报道了组蛋白驱逐是对PARPi治疗的一种即时细胞反应，并为靶向组蛋白供应途径以克服PARPi耐药性提供了一条有前景的途径。
