Team Uncovers How a DNA Repair Enzyme Reshapes Chromatin

Cells respond to DNA damage by activating repair processes, and blocking that repair machinery can be a useful cancer treatment strategy in tumors with genetic weaknesses tied to how they handle DNA damage. Researchers at St. Jude Children’s Research Hospital have now worked out a mechanism behind part of that repair process, a finding published in Molecular Cell that could carry implications for cancer treatment.

Among the first molecules to respond to DNA damage is the enzyme poly (ADP-ribose) polymerase, or PARP1, known for two main jobs: detecting the damage and sending a signal, through a process called poly (ADP-ribosyl)ation, that kicks off repair inside the cell. What hadn’t been clear was how PARP1 gets past the nucleosome, the tightly packaged structure that normally blocks access to DNA, in order to start that repair. Combining biochemical and cellular experiments, the St. Jude team worked out, for the first time, a direct role PARP1 plays in remodeling chromatin itself.

“Our study revealed a third, previously undescribed role of PARP1 in DNA damage repair, where we observed that the enzyme disassembles the nucleosome to facilitate chromatin accessibility so other downstream repair mechanisms can come in to do their job,” said corresponding author Hai Dao. “But, to our surprise, we observed that PARP1 disassembles the nucleosome in a very unique way.”

A nucleosome, the basic repeating unit that packages chromatin so DNA can fit inside the cell’s nucleus, is built from DNA wound around a symmetric core of eight histone proteins. The team found that PARP1 doesn’t break this structure apart evenly—instead, it asymmetrically removes two histone proteins next to the damage site, converting the nucleosome into a hexasome, a six-histone structure that partially opens up the DNA. That resulting hexasome then functions as a hub that pulls in the proteins needed to carry out repair at the damage site. 

A second, related surprise emerged around the C-terminal tail of histone H2A, a nucleosome component known to sometimes carry cancer-linked mutations. The researchers found that this tail directly controls how PARP1 disassembles the nucleosome, and that removing it made cells more sensitive to DNA-damaging treatments—raising the possibility that the remodeling process itself could play a role in disease development.

The team says mapping out this mechanism lays groundwork for more precisely targeted cancer therapies. “We are excited about the discovery because current PARP inhibitors target PARP catalytic activity broadly, so they shut down all PARP activity, which can have a toxic effect. By revealing a previously undescribed function of PARP1, it opens the possibility for future studies into therapeutics where we shut down certain kinds of PARP1-related enzymatic activity, like the remodeling activity,” Dao said. “That would be a new way of targeting the cells that depend on that activity.”