NASP modulates histone turnover to drive PARP inhibitor resistance

PARP inhibitors (PARPi) present a remarkable advance in the treatment of patients with homologous recombination (HR)-deficient tumors but resistance remains a challenge1-5. While most research has focused 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 PARP inhibition 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. Through functional genetic screens, we identified NASP as a key factor in maintaining the stability of evicted histones via its TPR motifs. NASP loss renders tumor 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 following PARPi exposure. 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. Overall design: Hi-C was performed on the following genotypes: Wild Type , ?BRCA1/53BP1 HAP1 cells. Cells were untreated or exposed to 1µM olaparib for 24 hours.