Image: Nanoparticles (in red) carrying microRNAs to an aggressive breast tumour in a mouse model. Credit: Joao Conde, Nuria Oliva, and Natalie Artzi
You might not realise that today is World RNA Day, as it was only in 2018 that a dedicated day on which to celebrate the ribonucleic acid (RNA) present in all living cells was introduced. In contrast, we’ve been annually acknowledging the importance of deoxyribonucleic acid (DNA) since 2003, when the National Human Genome Research Institute wished to commemorate 50 years since Watson and Crick announced their discovery of DNA’s double helix structure.
If we consider RNA and DNA as a partnership, RNA is arguably the John Watson to DNA’s Sherlock Holmes, the Bernie Taupin to DNA’s Elton John, the Paul Allen to DNA’s Bill Gates, and so on. After all, DNA might get the lion’s share of attention, but it needs RNA.
Most people are aware of DNA as the molecule that carries our genetic code, but RNA remains less widely understood. For a long time, it was believed that RNA served only as an intermediary between DNA and the proteins the body’s cells produce, so it was frequently overlooked. This idea was disputed a few decades ago, but our understanding of RNA still has far to go.
When asked why this was the case, Professor Vlad Pena – a Team Leader in Structural Biology at The Institute of Cancer Research – commented:
“The common perception that RNA receives less attention than DNA has both historical and technical reasons. The earlier models that described RNA as a mere intermediary have resulted in a DNA-centric perception of importance, which overshadows the significance of RNA. Scientific paradigms can survive for extended periods and become dogma, especially if widely accepted.
“Furthermore, the type of RNA that carries genetic information represents a small fraction of the total RNA in cells. This led to the misconception that most RNA was ‘junk’ of limited biological relevance.
“Finally, there are the technical reasons: RNA is more labile than DNA and more challenging to isolate and work with, which makes its investigation more difficult.”
Luckily, scientists are not deterred by this challenge, and they have increasingly shifted their focus from DNA towards RNA, with some describing the latter as being “much more fascinating” and “much more fun” to work on.
In the last few years, RNA has also entered the public arena, attracting much media coverage as a result of the many myths and concerns surrounding its use in Covid-19 vaccines.
What is RNA, and how does it differ from DNA?
Cells make two types of nucleic acid: RNA and DNA. We first became aware of nucleic acid back in 1869, when Frederick Miescher isolated DNA from cells and called it ‘nuclein’. Over time, scientists have learned that RNA differs from DNA in various ways, both structurally and functionally.
For instance, RNA is single-stranded, whereas DNA is double-stranded. DNA strands are long and take the shape of an organised double helix, making them more stable than RNA strands, which are relatively short and fold up to form complicated but functional shapes. In addition, while both molecules contain the nucleotides adenine (A), cytosine (C) and guanine (G), DNA’s fourth nucleotide is thymine (T) and RNA’s is uracil (U).
The RNA codon that initiates protein synthesis in cells is adenine, uracil, guanine, which is written as AUG. This is why we celebrate World RNA Day on 1 AUGust!
DNA serves as a store of genetic information, which is replicated before a cell divides so that each cell has its own copy. Alongside it are different types of RNA, each of which has its own role in the body. RNAs can be divided into coding RNAs, called messenger RNAs (mRNAs), and non-coding RNAs (ncRNAs).
Enzymes build mRNAs to complement the genetic information in DNA (transcription), and these molecules then transmit this information to the ribosomes in cells (translation) to allow protein synthesis. Each sequence of three nucleotides forms a codon, which provides the code for a particular amino acid or signals the stop point for transcription. Scientists are still investigating all of the roles of ncRNAs, but they include physically linking mRNA to the components of the protein being built and removing non-coding sequences of mRNA.
RNA’s role in transcription is crucial because any errors that occur can not only reduce the number of functional proteins in the body but also generate mutant proteins that can be harmful to the body.
Why is RNA important in cancer research?
As some types of cancer can run in families, scientists have long been aware that DNA mutations – both inherited and acquired – can significantly increase susceptibility to the disease. Genetic testing can identify individuals at risk, potentially giving them the opportunity to take preventive action. It also facilitates personalised medicine, whereby healthcare professionals base their treatment decisions on the person’s genetic makeup to maximise the likelihood of a good outcome.
Research into the human genome spans multiple types of cancer, so genomics is one of the ICR’s research themes.
Learn more about the ICR’s work in genomics
More recently, though, it has been confirmed that genetic factors can still pose a risk to those with healthy DNA. Research has shown that the altered activity of RNA, including its networks and binding proteins, can contribute to both the development and the progression of cancer.
For example, if RNA introduces errors during the transcription of a correct DNA sequence, this will affect which proteins are produced. It could lead to lower levels of cancer-killing proteins or higher levels of proteins that promote cancer cell proliferation. Another possibility is that changes to the function of certain RNA-binding proteins – proteins that bind to the RNA in cells and help control its activities – may interfere with their role as ‘gatekeepers’, stopping them from controlling RNA processes.
RNA therefore represents another route to understanding, preventing and treating cancer. With cancer remaining a leading cause of death, accounting for nearly one in six deaths worldwide each year, it is essential that we explore all such routes.
Where are we currently at with this research?
To get a better understanding of the research in this field, we spoke with Dr Paul Clarke, Team Leader of the RNA Biology and Molecular Therapeutics team in the Centre for Cancer Drug Discovery at the ICR. Although Dr Clarke has been interested in cancer since studying biology at school, his early postgraduate and postdoctoral studies were concentrated on understanding the RNA-protein interactions regulating the cellular sensors that detect viral RNA genomes or RNA intermediates of viral replication during a virus infection.
“Interestingly,” he said, “these pathways have recently come back into vogue [in cancer research], as it is becoming increasingly clear that activation of these pathways by some classes of cancer therapeutics, including inhibitors of RNA processing, may also provide routes to induce cancer cell death or immune responses to the cancer.”
Despite the clear appetite among scientists for research into RNA, this field is not without its challenges, which include the stability and delivery of RNA-based therapeutics.
Dr Clarke explained: “Compared with DNA, RNA has poor stability, and unless great care is taken during its preparation, RNA will quickly lose its structure and degrade. This characteristic makes RNA inherently difficult to analyse or to use as a therapeutic. In addition, the charged nature of RNA’s backbone greatly hampers its uptake into cells.”
Luckily, techniques are under development that may overcome these features. Scientists have also managed to address the challenges around RNA-binding proteins.
“RNA-binding proteins have long been regarded as undruggable,” said Dr Clarke, “largely due to their complex interactions with RNA. In addition, these proteins often consist of intrinsically disordered regions that lack discernible, druggable binding pockets that could be targeted by compounds. They also have conserved binding domains that can be shared by multiple RNA-binding proteins, and this may limit the discovery of selective inhibitors. However, thanks to scientific advances, RNA-binding proteins are showing increasing potential as therapeutic targets. In fact, drugs targeting different types of RNA-binding proteins are now entering early clinical studies.”
Will a better understanding of RNA change the treatment landscape in cancer?
It’s too early to know how much impact RNA research will have on cancer treatment, but scientists are investigating various approaches. Some are exploring using RNA as the actual treatment, either delivering it as part of a vaccine or using certain ncRNAs to block the translation of mRNA. Others are working on using small molecule therapeutics – drugs with a low molecular weight that can enter cells easily – to target and inhibit the activity of RNA-binding proteins.
ICR scientists are part of a team investigating a protein called RBM39, which removes non-coding sections of mRNA. By targeting RBM39 for destruction, the drug indisulam impairs the activity of mRNA, preventing excessive cell growth. It might be effective as a treatment in high-risk neuroblastoma.
Read the publication in the journal Nature Communications
Dr Clarke is excited by the momentum in RNA therapeutics. “It has re-ignited my interest in targeting the regulation of RNA processing and function in cancer,” he said. “My team is currently focusing on the discovery of compounds able to inhibit a class of RNA-binding proteins that influences the structure of RNAs that support the cancer state. We are also working on targeting an RNA-binding protein that regulates protein synthesis and cooperates with oncogenes during tumorigenesis.”
Professor Pena regards RNA biology as now being “at the forefront of molecular biology research”. He said: “The study of splicing and ncRNAs has revolutionised our understanding of RNA's significance beyond being a simple intermediary. We now see it as the molecular support of information processing in cells. It is the complexity of processing information that accounts for the complexity of life. Had RNA been only an ordinary copy of DNA, life could not go further beyond basic prokaryotes or even hardly pass an abiotic stage. I think RNA deserves the role of a cultural symbol more than DNA, whose importance stems more from historical reasons.”
On this World RNA Day, let’s celebrate RNA getting its moment in the spotlight and hope that RNA research will lead to better outcomes for everyone living with cancer.
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