Inside cells, some DNA is wound into tight packets, known as nucleosomes. Special enzymes bind to these compact packages of genetic material, helping to activate genes. But just how the crucial binding happens in three-dimensional space was unclear.
"For years, the research community has been at an impasse," Frank Pugh, director of the Penn State Center for Eukaryotic Gene Regulation, said in a prepared statement. "We were limited to only speculating how cellular proteins might bind to the nucleosome."
But getting the spatial specifics of the interaction among nucleosomes and binding proteins is important in the quest to better understand genetic processes—and diseases. "We needed to visualize how these enzymes are able to read such a complicated structure as the nucleosome," Song Tan, also at Penn State, said in a prepared statement.
Using x-ray crystallography, Tan and his colleagues were able to visualize the binding of a protein to nucleosomes in three dimensions for the first time.
The group selected RCC1, an enzyme that helps to separate chromosomes when a cell divides, to bind to fruit fly nucleosome core particles. "Our results showed that the RCC1 protein binds to opposite sides of the nucleosome—similar to pedals positioned on a tricycle [front] wheel," Tan said. From the x-ray crystallography, researchers created a three-dimensional computer model of the process. The results were published online August 25 in Nature (Scientific American is part of Nature Publishing Group).
"Now, with this structure, we are one step closer" to understanding how cells read DNA to regulate the activity of genes, Pugh said. It also lays groundwork for gaining a better understanding of how some enzymes might cause genes to misbehave.
"Our goal now is to determine the structures of other biologically and medically important chromatin enzymes bound to the nucleosome," Tan said. Such studies, he added, could "provide the basis for new therapeutics against human diseases such as cancer."
Image of protein and nucleosome courtesy of Song Tan Laboratory/Penn State University
Video animation of protein and nucleosome courtesy of Song Tan Laboratory/Penn State University