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NewsScientists at Penn State have mapped the first 3D structure of the cancer-linked BRD4 protein bound to a full nucleosome, revealing it can attach to chromosomes without the chemical signal previously thought to be required. Using cryo-electron microscopy, the team found BRD4 binds both modified and unmodified histones with nearly equal strength — a finding that could reshape how researchers approach cancer therapies targeting this protein.
Scientists at Penn State have captured the first detailed 3D structure of BRD4 — a protein linked to multiple cancers — bound to an entire nucleosome (the basic DNA-packaging unit in cells). Using cryo-electron microscopy (cryo-EM), the team found that BRD4 doesn't just latch onto chemically modified histones as previously believed; it also binds directly to DNA and, strikingly, to unmodified histones with nearly the same affinity.
This challenges a long-held assumption in the field: that a specific chemical tag (acetylation) on histone proteins was essential for BRD4 to bind to chromosomes. The new structure also shows BRD4 creating a kind of "welcome mat" — a platform that facilitates interactions with other proteins, shedding light on how it regulates gene activity.
Key Takeaways:
Why it matters: BRD4 is a high-priority drug target in oncology. Understanding its full binding behavior — including this unexpected histone-independent mechanism — could open new avenues for designing more precise and effective cancer therapies.
