This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: A new 3D structure of a cancer-linked protein bound to its cellular partner reveals details of how the protein binds to chromosomes and could offer insights for future disease treatments. The protein—BRD4—plays a critical role in how cells read, copy and repair DNA and helps determine how different kinds of cells are made; it has been linked to many types of cancer and is considered a promising target for future therapies.
The study, led by scientists at Penn State and published in the journal Molecular Cell, found that BRD4 can attach to DNA-packaging structures in cells even without a molecular signal long believed to be necessary for the interaction. "We were motivated to understand the basic biology of BRD4 and what it can teach us about the structure and function of this group of proteins," said Song Tan, Verne M. Willaman Professor of Molecular Biology in the Penn State Eberly College of Science and the leader of the research team.
"While the role of BRD4 in cancer was not our immediate focus, as we continue to build a better understanding of its function, we hope to reveal clues that could be used in the development of more effective treatments." BRD4 is a member of a family of proteins that contain structures called bromodomains. The protein uses these structures to bind to chromosomes, where BRD4 helps control when other genes are turned on or off. It was thought that BRD4 binds to the chromosome's repeating structure, called the nucleosome, when its bromodomains interact with proteins called histones in the nucleosome that have been modified by the addition of a chemical tag, the researchers explained.
"Previous studies of BRD4 structure had looked at it bound to a fragment of one of the modified histone proteins," Tan said. "We were keen to see if we could gain additional insight into its structure and function by imaging it bound to an entire nucleosome." The team used cryo-electron microscopy (cryo-EM), a powerful technique that can capture images at near-atomic resolution, to show that BRD4 bound to the modified histone, as expected, but it also bound directly to DNA in the nucleosome. The structure of BRD4 bound to the nucleosome also showed that when one of its bromodomains binds with a modified histone, the protein structure creates a platform for interacting with other proteins.
"BRD4 interacts with many other proteins to carry out its function; our 3D structure seems to show it laying out a welcome mat for these interactions," said Jiang Zhu, assistant research professor of biochemistry and molecular biology and co-first author of the paper. "This structural insight will help us begin to piece together exactly how this protein functions. It shows the benefit of imaging BRD4 in its biologically relevant context, bound to an entire nucleosome." The team then performed additional experiments to test whether BRD4 could still bind to a nucleosome in the absence of the chemical tags on the histones.
They found that BRD4 binds to unmodified histones with nearly the same affinity as it binds to modified ones. "This was a total surprise," said Erik M. Leith, who completed his doctorate in the biochemistry, microbiology and molecular biology graduate program at Penn State in 2025 and is co-first author of the paper.
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