One of those processes is called splicing, a mechanism by which non-coding gene sequences are removed and the remaining protein-coding sequences are joined together to form a final, mature messenger RNA (mRNA), which contains the recipe for making a protein.
For years, researchers have understood the roles played by the molecular machines that carry out the splicing process. But, as it turns out, one of those familiar components plays a new, and altogether unexpected role.
As senior author Gideon Dreyfuss, PhD, the Isaac Norris Professor of Biochemistry and Biophysics at the University of Pennsylvania School of Medicine and colleagues report in Nature, one of the splicing machinery's components called U1 has a second, equally important role in gene expression: To enable gene sequences to be read out into their RNA transcripts in their entirety, rather than have that process prematurely stopped. Dreyfuss is also a Howard Hughes Medical Institute Investigator.
The researchers revealed an unexpected function for U1 in protecting mRNA transcripts from premature termination in addition to and independent of its role in splicing.
As Dreyfuss puts it, "U1 is a guardian of the transcriptome." The transcriptome is the set of all RNA molecules in one cell.
U1 is one of a collection of RNA-protein complexes, called snRNPs, that recognize splicing junctions, excise non-coding gene sequences called introns, and join the remaining coding sequences called exons together. The Dreyfuss team previously showed that loss of SMN, a protein that helps assemble snRNPs and is deficient in individuals with the common neurodegenerative disease spinal muscular atrophy (SMA), results in altered snRNP levels and abnormal splicing.
SMN deficiency affects all snRNPs to one degree or another. The Dreyfuss team wanted to find out what would happen if just one snRNP was missing. They started with U1.
The team's expectation was that they would detect an increase in unspliced RNA transcripts, and indeed they saw evidence of that. But, to their surprise, the majority of the genes produced a very different and striking result. Their transcripts terminated prematurely and abruptly, generally within a relatively short distance from the transcription start site of the gene.
When they sequenced the ends of the resulting truncated RNAs, they found that they had been prematurely cleaved and tagged with a long string of nucleotide building blocks called adenine. This string is a hallmark of a process called cleavage-and-polyadenylation, which normally occurs at the end of a gene's RNA transcript. The lack of U1 was causing the cleavage/polyadenylation machinery to kick into gear early.
The implication, Dreyfuss says, is that U1's normal role, in addition to splicing, is to keep the cleavage/polyadenylation machinery in check until the RNA polymerase enzyme that synthesizes the transcript reaches its finish line. The researchers propose a model in which U1 binds throughout the nascent RNA transcripts, stymieing the cleavage/polyadenylation machinery that tags along with the moving polymerase complex. This in turn protects the many potential polyadenylation signals encountered along the way, and could explain the relative abundance of U1 in cells compared to other snRNPs. The additional U1 corresponds to the greater amount needed for its additional function.
"The transcripts are under constant threat from the cleavage/polyadenylation machinery," Dreyfuss explains. "This machinery doesn't patiently wait for the transcript to reach the end of the gene; rather, the nascent RNA transcripts are subject to becoming attacked by this machinery. It's a constant danger they face, and the U1 snRNP suppresses it."
It is, he says, "a novel role" for U1, and a critical component for correctly making mRNA. "It is essential for the integrity of the transcriptome, the landscape of all mRNA molecules in the cell," he concludes.
Other coauthors on the paper include Penn researchers Daisuke Kaida, Michael Berg, Ihab Younis, Mumtaz Kasim, Larry Singh, and Lili Wan. The research was funded by the Association Française Contre les Myopathies and the Howard Hughes Medical Institute.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $3.6 billion enterprise.
Penn’s School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools, and is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $367.2 million awarded in the 2008 fiscal year.
Penn Medicine’s patient care facilities include:
The Hospital of the University of Pennsylvania – the nation’s first teaching hospital, recognized as one of the nation’s top 10 hospitals by U.S. News & World Report.
Penn Presbyterian Medical Center – named one of the top 100 hospitals for cardiovascular care by Thomson Reuters for six years.
Pennsylvania Hospital – the nation’s first hospital, founded in 1751, nationally recognized for excellence in orthopaedics, obstetrics & gynecology, and psychiatry & behavioral health.
Additional patient care facilities and services include Penn Medicine at Rittenhouse, a Philadelphia campus offering inpatient rehabilitation and outpatient care in many specialties; as well as a primary care provider network; a faculty practice plan; home care and hospice services; and several multispecialty outpatient facilities across the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2009, Penn Medicine provided $733.5 million to benefit our community.
Karen Kreeger | EurekAlert!
How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology