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Researchers at St. Jude Children's Research Hospital have discovered a previously unknown function of PARP1, a key enzyme in DNA repair. Beyond signaling for repairs, the enzyme physically restructures DNA packaging to make damage sites accessible. This finding could pave the way for more precise PARP inhibitor therapies with fewer toxic side effects.
Scientists at St. Jude Children's Research Hospital have uncovered a surprising third role for PARP1, an enzyme long known as one of the first responders to DNA damage. Beyond sensing damage and triggering repair signals, PARP1 also physically dismantles the nucleosome — the protein-and-DNA packaging unit that keeps genetic material compacted inside cells — to make the damage site accessible for repair machinery.
Specifically, researchers found that PARP1 asymmetrically removes two histone proteins near the damage site, creating a six-protein "hexasome" structure that partially opens the nucleosome and acts as a hub for recruiting other repair proteins. They also discovered that a component of histone H2A controls this process, and that its removal increases sensitivity to DNA-damaging therapies — hinting at a possible link to cancer development.
Key Takeaways:
Why it matters: PARP inhibitors are already used in treating cancers like BRCA-mutated breast and ovarian cancer. Understanding this new mechanism could help scientists design next-generation therapies that selectively block only the harmful aspects of PARP1 activity — potentially improving efficacy while reducing toxicity.
