Wayne State University researcher discovers dynamic nature of gene editing enzyme
DETROIT– The heart of one of nature’s gene editing enzymes has at least three different forms, according to a paper just published by a Wayne State researcher. The discovery is essential for understanding how protein production works – and why it sometimes fails.
David Rueda, Ph.D., assistant professor of chemistry in the College of Liberal Arts and Sciences, was published in the November edition of Nature Structural & Molecular Biology for uncovering and characterizing dynamics of two key molecules in the spliceosome, an enzyme critical to the body’s gene editing process.
The study focused on RNA, a nucleic acid similar in composition to DNA, which is sometimes referred to as DNA’s “chemical cousin.” RNA’s single chain of nucleotides contains the code used to build proteins in cells. The role of the spliceosome is to cut out unneeded portions of the RNA chain and paste the remaining regions together, and this edited RNA strand becomes the “recipe” for the production of a protein.
Spliceosomal errors can be lethal to the cell and have been linked to numerous cancers and neurodegenerative disorders. “Even a single nucleotide error can impair normal cell functioning,” Rueda said. “Errors in splicing have been linked to cancer, Alzheimer’s and other neurodegenerative diseases. That’s why it is so important to understand how the process works – so we can prevent it from working incorrectly.”
In order to gain a fundamental understanding of spliceosomal function, Rueda focused on RNA molecules U2 and U6, which are essential for catalyzing the cutting and pasting processes of the spliceosome. “The first step toward understanding how RNA works is learning the three-dimensional form of the molecule and its dynamics,” Rueda said.
Previous studies on the structure of U2 and U6 yielded different results, with one suggesting the molecule has a 3-helix structure and another suggesting a 4-helix structure. Using single molecule spectroscopy and florescent dyes, Rueda’s lab characterized the structure U2 and U6. They found that the structures adopt both previously suggested forms and they observed a third, previously unseen structural conformation. “Our lab is the first to show these two RNA molecules, which are the heart of the spliceosome, are dynamic in nature,” he said. “They switch from one form to another, which we suspect is related to different activation states.
“In over 30 years of research on the spliceosome, this is the first time all three structural conformations and their dynamics have been characterized,” Rueda said. “Just like mechanics need to understand how an engine works normally before they can repair a damaged one, this discovery provides important details about the function of this critical biological step in cellular protein formation. Greater understanding of the spliceosome could lead to new ways to prevent and treat devastating diseases for which there are currently no cures.”
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