Most people are familiar with the twisted ladder shape of DNA’s double helix. But sometimes, for reasons no one fully understands, the normal double helix structure is turned on its head. Duke University School of Medicine researcher Hashim Al-Hashimi, PhD, aims to create a map of these novel structures in the human genome.
His proposal to do so has been selected for $1 million in funding by the G. Harold and Leila Y. Mathers Foundation.
Al-Hashimi's project builds upon his 2011 discovery that the double helix structure of DNA base pairs intermittently change their configuration from the familiar arrangement described by Watson and Crick to a flipped version called a Hoogsteen base pair. "If you think of the structure of the DNA double helix as a spiral staircase, a Hoogsteen base pair can best be described as taking the steps and flipping them 180 degrees like a pancake," says Al-Hashimi, James B. Duke Professor of Biochemistry and Chemistry.
Al-Hashimi's lab, in collaboration with several other researchers at the Duke University School of Medicine as well as Ohio State University, will develop and apply techniques in dynamic nuclear polarization-nuclear magnetic resonance imaging and genome sequencing to map the regions in which these novel structures most often occur.
"The generous support of the Mathers Foundation will help us provide, if you will, a zip code by which we may be able to understand which DNA regions act differently than others," he says. "Once we do that, we may be able to understand, for example, why certain regions of the DNA are more prone to mutations."
Scientists aren't sure what Hoogsteen base pairs are doing in the genome, but Al-Hashimi suspects that one of their functions is to make the DNA base pair more flexible and adaptable. He hopes that mapping their occurrence will improve our fundamental understanding of genome architecture and gene expression, as well as disease processes such as cancer.
The mission of the G. Harold and Leila Y. Mathers Foundation is to advance knowledge in the life sciences by sponsoring scientific research and applying learnings and discoveries to benefit mankind. Basic scientific research, some with potential translational application, is central to this goal.
Angela Spivey, Duke Health Development and Alumni Affairs
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