Scientists led by a group at the University of Leicester say they have made a breakthrough advance that could pave a new route for the development of anticancer drugs. Ian Eperon, Ph.D., and Cyril Dominguez, Ph.D., from the University of Leicester’s Institute of Structural and Chemical Biology, and colleagues published a study (“Identification of G-Quadruplexes in Long Functional RNAs Using 7-Deazaguanine RNA”) in Nature Chemical Biology that described a new technique to analyze the RNA step in expressing our genetic code.
“Our research aims at understanding how four-stranded RNA structures called G-quadruplexes affect cellular processes such as RNA splicing. In this research, we describe a novel method that, for the first time, allows us to show that G-quadruplexes form in long RNAs and in conditions where the splicing reaction can take place,” said Dr. Dominguez, also of the Department of Molecular and Cell Biology.
G-quadruplexes are specific structures formed when a piece of DNA or RNA folds into a four-stranded structure. DNA G-quadruplexes have been shown to be associated with diseases such as cancer, and many small molecules called G-quadruplex binders have been developed as putative novel anticancer drugs, the best example being Quarfloxin, which reached a Phase II clinical trial. RNA G-quadruplexes are also believed to play important roles in cancers, but to date there are no straightforward methods to prove that they exist in cells. If they form and do control RNA splicing, then the design of molecules that bind them would be a new route for the development of anti-cancer drugs.
According to Dr. Eperon, “Our novel method, FOLDeR, will allow RNA scientists to investigate the existence of G-quadruplexes in physiological conditions, allowing a better understanding of their role in cellular processes. It is particularly interesting that the RNA we have been studying is one that plays an important role in some cancers. When the RNA is spliced using one set of sites, it produces a protein favoring cell survival. This is a problem for cancer treatments, many of which work by damaging growing cells in the hope that they will then die. However, when an alternative set of sites is used, the RNA produces a protein that encourages cell death. We have shown that G-quadruplexes form near the alternative sites, and our hope is that we can target these to shift splicing toward the pro-death pattern.”
In a follow-up paper, the team will report their work on drugs that exploit this structure. “This publication is crucial for us to obtain further funding and carry on with this topic,” explained Dr. Dominguez. “Our next step is to investigate the effect of G-quadruplex binders on RNA splicing and use this knowledge to design novel drugs with a high degree of specificity for cancer cells.”
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