G-quadraplex formation and the development of cancers

An online publication in Nature Nanotechnology this week by Kent State University researchers and their colleagues at Kyoto University in Japan, however, may offer new understanding about what turns good cells bad.
Hanbin Mao, Ph.D., professor of chemistry and biochemistry in Kent State’s College of Arts and Sciences, co-authored a paper with his graduate students, Prakash Shrestha and Sagun Jonchhe, along with four Kyoto University colleagues, titled “Confined Space Facilitates G-quadruplex Formation,” which was published March 27 on the esteemed journal’s website. The article discusses the genetic factors that influence formation of cancer cells.

“Traditionally, DNA has a two-strand shape — the double helix — and its purpose is to code the proteins that form life,” Mao said. “But recently, people have discovered that some DNA has four strands, and we call this the G-quadruplex. This is associated with the inhibition of cancer cells.”

However, while most G-quadruplex DNA is beneficial, Mao said some strands go bad and such mutations actually will enable cancer cell growth. To understand why this happens, scientists first had to learn why DNA sometimes develops into four-strand structures.

All DNA is generated by enzymes and operates like an assembly line. However, Mao said, there comes a point where DNA makes a decision to form a double helix or a quadruplex. He said most DNA takes the two-strand route simply because it is the easiest path.

Mao said nanometer-sized (one billionth of meter; 25,400,000 nanometers = 1 inch) spaces inside the enzymes are where these formations occur. The inability to mimic these spaces in laboratory settings has prohibited deeper study of the G-quadruplex formation. That is, until now.

With help from chemists and engineers at Kyoto University in Japan, Kent State’s Mao and graduate students Shrestha and Jonchhe used “DNA origami” to create a “nano cage.” They accomplished this through single-molecule mechanochemical sensing — a technology Mao’s lab developed in 2014. Over the past few years, he has published several studies involving the use of “laser tweezers,” a tool that provides the ability to hold micrometer- and nanometer-sized biological materials in place.

That technology allowed Mao to create 6-by-6 nanometer-sized cages, then observe how DNA folded into different shapes inside the space.

“It’s easier for the DNA to fold inside the cage,” he said. “It folds to adapt to the small space, and here DNA naturally folds into the G-quadruplex.”

He said the process occurs two to three orders of magnitude faster inside the cage than out, folding 100,000 per second — a speed that makes forming G-quadruplex as fast and easy as forming a double helix.

“With that observation, we may follow the fate of the cell to be cancerous or healthy,” he said. “So we can perhaps learn how to introduce molecules or chemicals to interfere with that process.”

He said scientists can use ligands — bonded molecules — to facilitate this effect with greater potency, thereby reducing the likelihood that cancer cells will form.

“We can prevent or better treat cancer by stabilizing G-quadruplex structures,” Mao said.

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