(MEMPHIS, Tenn. – Month XX, 2026 ) When DNA is damaged, cellular processes respond and repair the DNA. Inhibiting DNA damage repair can be therapeutically beneficial in cancers with genetic vulnerabilities related to DNA damage response. Scientists at St. Jude Children’s Research Hospital have uncovered a mechanism behind how this process works, which may have implications for cancer treatment. The results were published today in Molecular Cell.
One of the “first responders” to begin DNA damage repair is the enzyme poly (ADP-ribose) polymerase (PARP1). PARP1 has two known primary functions: to sense DNA damage and send a signal through protein poly (ADP-ribosyl)ation that initiates DNA repair inside a cell. However, how PARP1 overcomes the nucleosome barrier to begin DNA repair was unknown. Using a combination of biochemical and cellular testing, researchers at St. Jude dissected a direct function of PARP1 in chromatin remodeling for the first time.
“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 , PhD, St. Jude Department of Chemical Biology & Therapeutics assistant member. “But, to our surprise, we observed that PARP1 disassembles the nucleosome in a very unique way.”
PARP1’s unique function in facilitating DNA repair
The nucleosome, which is the repeating structural unit of chromatin that compacts DNA to fit inside a cell’s nucleus, consists of DNA wrapped around a symmetric core of eight histone proteins.
Using biochemical and cellular tests, the researchers found that PARP1 asymmetrically evicts two histone proteins next to the site of DNA damage. This in turn leads to the formation of a hexasome (a nucleosomal structure that uses six histone proteins instead of eight). This mechanism partially opens the nucleosome, and the modified hexasome then serves as a bifunctional hub for recruiting proteins to the site of DNA damage to facilitate repair.
A related, and additionally surprising finding was revealed when the team observed that a part of histone H2A, called the C-terminal tail — a component of the nucleosome that can contain cancer-associated mutations — molecularly controls PARP1-mediated nucleosome disassembly. The investigators showed that removal of the H2A tail increases sensitivity to DNA-damaging therapies, raising the possibility that the remodeling activity itself could contribute to disease formation.
Future therapeutic implications for PARP1 inhibitors
By uncovering the mechanisms behind PARP1-mediated DNA damage repair, the team has provided foundational insights that could lead to more targeted therapeutic approaches.
“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,” said Dao. “That would be a new way of targeting the cells that depend on that activity.”
Authors and funding
The study’s co-first authors are Ashish Verma and Changlei Zhu, St. Jude. Other authors are Bernadette Truong, Silvija Bilokapic, Rebekah DeVries, Aaron Pitre, Younus Bhat, Anang Shelat and Mario Halic, St. Jude.
The study was supported by grants from the NIH/NIGMS (R35GM160211) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
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St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped increase overall childhood cancer survival rates from 20% to more than 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org , read St. Jude Progress, a digital magazine , and follow St. Jude on social media at @stjuderesearch .
Molecular Cell
Experimental study
Cells
PARP1 directly disassembles nucleosomes to regulate DNA repair
23-Oct-2026