An international research team led by the University of Leicester has made a breakthrough advance in understanding about RNA that could pave a new route for the development of anti-cancer drugs. This research is published in Nature Chemical Biology.
Professor Ian Eperon and Dr Cyril Dominguez from the University of Leicester’s Institute of Structural and Chemical Biology led the team that developed a new method to analyse the RNA step in expressing our genetic code. Dr Dominguez, of the Department of Molecular and Cell Biology, said: “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.”
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 anti-cancer drugs, the best example being Quarfloxin that 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.
During the process of gene expression, DNA is transcribed to RNA molecules that are in turn translated to produce proteins. RNA splicing is an essential step in producing the finished messenger RNA and the RNA copied from one gene can be spliced in different ways. This is how the 20,000 human genes can produce around 130,000 proteins.
This process is highly regulated and defects in its regulation are a common cause of many diseases, including spinal muscular atrophy and some cancers.
Professor Eperon said: “Our novel method, footprinting of long 7-deazaguanine-substituted RNAs (FOLDeR), will allow RNA scientists to investigate the existence of G-quadruplexes in physiological condition 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 favouring 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 towards the pro-death pattern.”
This is a major step forward in the G-quadruplex research field. In a follow-up paper, the team will report their work on drugs that exploit this structure.
Citation: Carika Weldon, Isabelle Behm-Ansmant, Laurence H Hurley, Glenn A Burley, Christiane Branlant, Ian C Eperon & Cyril Dominguez. “Identification of G-quadruplexes in long functional RNAs using 7-deazaguanine RNA” Nature Chemical Biology (2016).
Research funding: MRC Career Development Award, Bank of Butterfield Foundation
Adapted from press release by University of Leicester