Scientists believed that PARPi work mainly by causing DNA breaks, but in this new study, researchers show that they also disturb the way DNA is packaged inside cells. DNA is normally tightly wrapped around proteins called histones, like thread around a spool. PARPi cause histones to temporarily loosen their grip on the DNA, leaving it more exposed and fragile. To survive, cancer cells must quickly catch these displaced histones, store them safely, and put them back in place.
The team discovered that cancer cells use a kind of ‘supply chain’ for this job. “We were looking for early changes in the cell after PARP inhibition and stumbled upon this hidden vulnerability,” says researcher Sarah Moser, postdoc in the group of Jos Jonkers. The process works in three steps: first, INO80 removes the histones from the DNA. Then NASP, a ‘histone chaperone’ that stores and protects histones, keeps them safe until they are needed again. Finally, PARP1, and additional proteins put the histones back in place. “Cancer cells heavily rely on this INO80-NASP-PARP1 axis to meet their increased demand for histones, particularly under high rates of DNA replication and DNA damage induced by chemotherapeutics,” explains Abdel Mazouzi, postdoc in the group of Thijn Brummelkamp.
When NASP is missing, this recycling chain collapses. Histones pile up in the wrong places, DNA damage accumulates, and cancer cells, whether PARPi-naïve or already resistant, become hypersensitive to the drug. “Suddenly, cancer cells have to work hard to store and recycle these displaced histones to survive,” says Moser. “By disrupting histone recycling, we can push even the resistant cancer cells past their breaking point.”
Removing NASP restored PARPi sensitivity and slowed cancer growth in cell and mouse models. While this work is still in the laboratory phase, it highlights a promising new strategy to extend the effectiveness of PARPi therapy and to better understand one of oncology’s toughest challenges.
Research at the Netherlands Cancer Institute is financially supported by KWF Dutch Cancer Society and the AVL Foundation.