One of those RNPs is telomerase, an enzyme that maintains chromosome integrity. In the March 25, 2012, advance online edition of Nature, researchers at the Stowers Institute for Medical Research report how the RNA TER1, a component of telomerase, is sculpted to favor interaction with its protein partner. Two ring-like proteins sequentially slip onto unprocessed TER1 RNA and hold it while it is clipped to the optimum size, folded, and capped.
That processing is essential: without it TER1 could not engage its protein partner to form the active telomerase RNP. The finding not only deepens our understanding of RNA biochemistry but also suggests novel pharmaceutical approaches to cancer and diseases of aging.
"Cancer cells are exquisitely dependent on telomerase," says Stowers associate investigator and Howard Hughes Medical Institute Early Career Scientist Peter Baumann, Ph.D., the study's senior author. "Drugs inhibiting telomerase could be a new class of cancer chemotherapeutics with far fewer side effects than drugs in use." Currently, biotechnology and pharmaceutical companies are actively seeking clinically useful telomerase inhibitors.
Most RNA strands—including the intermediary or "messenger" RNAs—undergo splicing, analogous to editing a film. The universal snipper is a humongous complex called the spliceosome, which usually touches down on an RNA strand, makes two cuts, and then pastes the new ends together. But in a 2008 Nature study, the Baumann group reported a surprising finding. "We showed that the spliceosome acts to process TER1," he says. "But instead of cutting twice and pasting, it made a single cut and stopped."
To determine what restrained the spliceosome from making a second cut, Baumann's group analyzed TER1 RNA in the yeast Schizosaccharomyces pombe. They found that two protein complexes called Sm and Lsm latched onto TER1 RNA in a mutually exclusive fashion as the RNA matures. Interestingly, Lsm-bound TER1 RNA showed the most efficient telomerase activity, hinting that the Sm ring slips on first.
For further analysis they enlisted the aid of Stowers' assistant investigator Marco Blanchette, Ph.D., an RNA splicing expert. The team confirmed that indeed Sm bound immature TER1 RNA, prompting the incoming spliceosome to snip off everything to its "right". Once that cut was made, Sm appeared to promote formation of a protective tri-methylated "cap" on the "left" end of the TER1 transcript, thus stabilizing it. At that point the Sm ring slipped off and was replaced by Lsm, facilitating recruitment of TER1's catalytic protein partner.
This work shows that the marriage of RNA and protein telomerase partners requires a two-step ritual attended first by Sm and then by Lsm proteins. The presence of Lsm in preparations of the active enzyme also suggests that it lingers after the ceremony to protect mature Ter1 RNA from RNA-damaging enzymes.
Determining what the evolutionarily conserved Sm and Lsm proteins do is a significant contribution to RNA biology, says Wen Tang, a graduate student in the Baumann lab who led the study. "People discovered these proteins 20 years ago and knew they were essential for RNA processing," says Tang. "Right now we don't know whether Sm and Lsm participate in processing of telomerase in human cells. Other members of the lab are looking into that."
Understanding how telomerase works in human cells is vital because of its connection to seemingly unrelated diseases. Not only because cancer cells depend on its activity, but in a fascinating "converse", mutations that inactivate telomerase are seen in a degenerative condition called dyskeratosis congenital (DKC), in which patients show signs of premature aging in some organs.
"People have looked for mutations in telomerase components in individuals with DKC and found them in only about half of those patients," says Wen Tang. "This work identifies novel telomerase components that likely affect normal enzyme function." Those components could provide novel targets potentially useful to diagnose or treat DKC.
Baumann agrees that knowing how to tinker with TER1 biogenesis has therapeutic potential in several contexts. But he is equally happy that the new work adds to scientists' appreciation of RNA complexity. "This paper fills in the blanks between transcription of the TER1 RNA subunit and formation of an active telomerase complex," he says. "We also hope it provides a more complete picture of TER1 biogenesis in future textbooks."
Ram Kannan of the Baumann lab also contributed to the paper.
The work was supported in part by the Howard Hughes Medical Institute and the American Heart Association.
About the Stowers Institute for Medical Research
The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife Virginia opened the Institute in 2000. Since then, the Institute has spent over 800 million dollars in pursuit of its mission.
Currently the Institute is home to over 500 researchers and support personnel; over 20 independent research programs; and more than a dozen technology development and core facilities.
Gina Kirchweger | EurekAlert!
'Y' a protein unicorn might matter in glaucoma
23.10.2017 | Georgia Institute of Technology
Microfluidics probe 'cholesterol' of the oil industry
23.10.2017 | Rice University
Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
23.10.2017 | Event News
17.10.2017 | Event News
10.10.2017 | Event News
23.10.2017 | Life Sciences
23.10.2017 | Physics and Astronomy
23.10.2017 | Health and Medicine