Unlocking odd DNA structure could open up new approaches for treating cancer

Sean Kerwin

An unusual form of DNA, G-quadruplex, is known to exist under laboratory conditions, but a research team led by Sean Kerwin of the Department of Chemistry and Biochemistry at Texas State University has developed an innovative technique to detect if it exists naturally within human cells, and to determine what role it may play in the development of cancer.

The research team, comprised of Kerwin along with Dominic McBrayer, University of Nevada-Reno, Michelle Schoonover, Syneos Health Clinical Solutions, Kimberly J. Long, University of Texas at Austin and Ruby Escobedo, Texas State, have published their findings, "N-Methylmesoporphyrin IX Exhibits G-quadruplex Specific Photocleavage Activity" in the journal ChemBioChem (www.onlinelibrary.wiley.com/doi/abs/10.1002/cbic.201900002). Research funding was provided by the Cancer Prevention and Research Institute of Texas. 

Unlike the familiar double-helix form of DNA, the G-quadruplex form is comprised of a strand of DNA that wraps around itself to form layered tiers. It is associated with oncogenes – genes that can lead to cancer when activated.  

"The vast majority of DNA inside your cells looks like the double-helix, but we're discovering that sequences of DNA can adopt some unusual structures," Kerwin said. "G-quadruplex is the structure formed by a sequence in a promoter for the c-myc oncogene.

"This is a DNA structure we know we can form in a test tube. The $64 million question is, is this actually formed in your cells? Almost more importantly, if it is formed, what is it doing? Is it controlling the transcription of this oncogene?" he said. "The tool that we've developed is going to answer that question for us."

That tool is a tiny molecule known as N-Methylmesoporphyrin IX (NMM) that can penetrate cells and bond with G-quadruplex while ignoring double-helix DNA. When irradiated with light, NMM will cleave, or break up, the DNA structure, the remains of which can then be readily detected. NMM works with visible light, but the researchers hope to refine it to respond to infrared light, which is more effective at penetrating the body.  

"If we see cleavage in a cell, that means there was a quadruplex there. We can ask, 'Is this structure formed in the c-myc promoter responsible for keeping that gene off?'" Kerwin said. "If it is, we have a bona fide target for fighting cancer, because we could design molecules to stabilize the (quadruplex) structure and keep c-myc turned off and prevent cancer cells from becoming cancer cells.

"We're also intrigued because there are other roles these G-quadruplex structures have been proposed to play, in terms of the genetic instability that leads to cancer," he said. "There are certain hot spots in our genome that are known to undergo translocations, which are found in many types of cancer. Correlation is not causality, but we're thinking perhaps the formation of G-quadruplex structures has something to do with the propensity of those sequences to undergo the genetic rearrangements. We can use our molecule to test that."

If the technique proves successful, the same approach might be used to identify other molecules that bond with the distinctive quadruplex structures associated with different oncogenes. This could potentially lead to new avenues of cancer treatment, such as designing small, drug-like molecules that recognize and target specific sequences that are unique in the entire genome.