Building understanding of gene activity regulation

9 March 2020

A team of scientists in the United States, led by principal investigator Dr Anthony K L Leung (Croucher Scholarship 1999), has revealed a process in cells that may remove tangled ribonucleic acids (RNAs), a discovery that could eventually help researchers understand how some diseases develop and progress.

Researchers at Johns Hopkins Bloomberg School of Public Health have discovered a fundamental mechanism that regulates gene activity in cells, as reported in a recent news release from the School.

The mechanism targets RNA, which plays an important role in cellular activity. It effectively silences or reduces the effect of certain active genes as a basic cellular regulatory or quality-control system, and may act as a defence against viruses.

The discovery, published in Molecular Cell, is a significant addition to understanding how gene activity is regulated, and may ultimately lead to new medical treatments.

When genes are active, they are copied into strands of RNA. These RNA strands perform cellular functions on their own or are translated into proteins. The new mechanism destroys RNA strands that have excessively folded over and stuck to themselves to form knots, hairpins, and other structures, the release stated. These highly structured RNAs can occur during normal processing but may also be caused by misfolding.

Medical research could benefit from the discovery because many human disorders, including cancers and neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) and Huntington disease-like syndromes, involve failures of normal RNA regulation and/or the accumulation of abnormally folded or tangled RNA in affected cells.

Leung, an Associate Professor in the Department of Biochemistry and Molecular Biology at the Bloomberg School, said: “We know that there are mechanisms to clear misfolded proteins from cells – possibly this newly uncovered mechanism is involved in clearing misfolded RNAs.”

The discovery might also help scientists understand how normal cells keep themselves healthy as RNA structure forms can play a role in cells maintaining cellular equilibrium, he added.

Most regulatory and quality-control mechanisms that modulate the levels of RNAs in cells target RNAs containing specific sequences of nucleotides – the building blocks of RNAs. The new mechanism is unique in that it recognises not sequences but a broad variety of structures formed where RNA strands, which are relatively sticky, have folded back on to themselves.

Leung and his team discovered the new mechanism while investigating a protein called UPF1, which is known to work in other RNA regulation pathways. They found that UPF1 and a partner protein called G3BP1 work together in the new mechanism, targeting only RNAs that contain a high level of structures.

When the researchers depleted UPF1 or G3BP1 from cells to shut off the new mechanism, levels of highly structured RNAs rose sharply. The team also confirmed that the new mechanism, which they call structure-mediated RNA decay, is distinct from all other known RNA-removal mechanisms and works across different types of RNA throughout the genome.

“Based on further analyses, we predict that this structure-mediated RNA decay pathway could regulate at least one-fourth of human protein-coding genes and one-third of a class of non-coding genes called circular RNA,” Leung said.

Leung and his colleagues are now following up to determine how this RNA decay mechanism actually targets and destroys RNAs. They are also investigating why this mechanism exists. Its functions, they speculate, may include the regulation of specific functional variants of protein-coding RNAs as well as the general disposal of RNAs that have acquired excessive loops and other structures.

The new mechanism may even have an antiviral role. “Some single-stranded RNA viruses that are highly structured, such as poliovirus, have ways to get rid of the G3BP1 protein when they infect a cell,” Leung said. “Possibly that’s because this G3BP1-UPF1 RNA-decay pathway is otherwise a major threat to them.”

Scientist and inventor Dr Anthony Leung is an expert in RNA, ADP-ribosylation, and proteomics. Leung completed his four-year Master’s degree in Biochemistry at Exeter College, University of Oxford, and his PhD in Biochemistry from the University of Dundee, under the guidance of Dr Angus Lamond. In 2004, Leung was awarded a Human Frontier Science Program Long-term Fellowship and, in 2007, received a Special Fellowship from the Leukemia & Lymphoma Society to carry out postdoctoral research on microRNAs under the mentorship of Nobel Laureate Dr Phillip Sharp at MIT. In 2010, he held a secondary postdoctoral appointment with Dr Paul Chang at MIT, investigating ADP-ribosylation. Leung started his lab as an Assistant Professor in the Department of Biochemistry and Molecular Biology at Johns Hopkins University in 2011, and is currently an Associate Professor there.

To view Dr Leung’s Croucher profile, please click here.