NASP modulates histone turnover to drive PARP inhibitor resistance
The use of PARP inhibitors (PARPi) presents a remarkable advance in the treatment of patients with homologous recombination (HR)-deficient tumors, however resistance remains a challenge due to genomic instability. While most research focuses on the downstream consequences of PARPi exposure to tackle resistance, the immediate impact of PARP inhibition on the chromatin environment and its contribution to PARPi toxicity remains elusive. Here, we show that chemical or genetic perturbation of PARP1 induces histone release from the chromatin. This presents a vulnerability of PARPi-resistant cancer cells, which are addicted to histone homeostasis mechanisms to sustain elevated DNA replication rates and survival. Using functional genetic screens, we identified NASP as a key factor in maintaining histone turnover via its TPR motifs. NASP loss renders tumor cells hypersensitive to PARPi treatment in vitro as well as in vivo, impairs replication fork progression and elevates levels of replication-associated DNA damage. Our data highlight essential roles for PARP1 activity and the chaperoning function of NASP in histone turnover, preventing 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.