NASP调节组蛋白转换以驱动PARP抑制剂耐药性，这一成果由荷兰Oncode研究所Jos Jonkers研究小组经过不懈努力而取得。相关论文于2025年8月13日发表在《自然》杂志上。

在这里，课题组研究人员发现PARP抑制诱导组蛋白从染色质释放。这表明PARPi耐药癌细胞的脆弱性，这需要组蛋白稳态机制来维持DNA复制率和存活率的升高。通过功能性遗传筛选，小组发现NASP是通过其TPR基序维持被驱逐组蛋白稳定性的关键因素。在体外和体内，NASP的缺失使肿瘤细胞对PARPi治疗过敏，损害复制叉的进展并提高复制相关DNA损伤的水平。

此外，NASP与INO80复合物和PARP1的伴随活性一起作用，确保有效的组蛋白转换，防止致命DNA损伤的积累。总的来说，他们的工作报告了组蛋白驱逐作为PARPi治疗的直接细胞反应，并为靶向组蛋白供应途径克服PARPi耐药性提供了一条有希望的途径。

研究人员表示，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。尽管大多数研究都集中在PARPi暴露于水稻抗性的下游后果上，但PARP抑制对染色质环境的直接影响及其对PARPi毒性的贡献仍然是未知的。

附：英文原文

Title: NASP modulates histone turnover to drive PARP inhibitor resistance

Author: 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., Vlker-Albert, Moritz, Mattiroli, Francesca, Brummelkamp, Thijn R., Mazouzi, Abdelghani, Jonkers, Jos

Issue&Volume: 2025-08-13

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 challenge1,2,3,4,5. 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.

DOI: 10.1038/s41586-025-09414-z

Source: https://www.nature.com/articles/s41586-025-09414-z