Check out the full story here: rdcu.be/eGm9f

Thank you so much for your help and probably the fastest collaboration in history!

@akhalizieva.bsky.social @milokaptein.bsky.social @icrlordlab.bsky.social @fmattiroli.bsky.social @thijnbrummel.bsky.social and all our blueskyless collaborators

I am also extremely thankful to my fellow lab members at @nkinl.bsky.social and our internal and external collaborators, whose expertise and dedication brought this project over the finish line. (8/8)

This project has been a truly exciting chapter of my PhD journey and I am deeply grateful to everyone involved. A heartfelt thank you to my mentors, @josjonkers.bsky.social and @amazouzi.bsky.social for their guidance in solving the histone puzzle.

💡 Take-home: Histone eviction is an immediate response to PARPi treatment and cancer cells are require an INO80–NASP–PARP1 axis for survival. Targeting histone turnover could therefore overcome drug resistance. (7/8)

However, NASP cannot do it all. It is supported by (1) the INO80 complex which remodels chromatin to evict histones, (2) which NASP then stabilises and stores and (3) PARP1 and other factors help reincorporate them. (6/8)

Lose NASP and even resistant tumor cells become resistant to PARPi. (5/8)

What are the factors mediating this histone release? To answer this we performed genome-wide genetic screens and identified NASP, a histone chaperone, as essential for handling these evicted histones. (4/8)

The answer was puzzling: Histones got kicked off the chromatin upon PARPi exposure. These free histones must be stored & recycled, otherwise cancer cells struggle to survive. (3/8)

PARP inhibitors (PARPi) have clearly been a game changer for homologous recombination-deficient tumours, but therapy resistance remains a challenge. The impact of PARPi on DNA integrity has been very well described, but we wondered what happens to the chromatin environment? 🧬 (2/8)