Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


A double ring ceremony prepares telomerase RNA to wed its protein partner

Few molecules are more interesting than DNA—except of course RNA. After two decades of research, that "other macromolecule" is no longer considered a mere messenger between glamorous DNA and protein-synthesizing machines. We now know that RNA has been leading a secret life, regulating gene expression and partnering with proteins to form catalytic ribonucleoprotein (RNP) complexes.

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!
Further information:

More articles from Life Sciences:

nachricht First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife

nachricht Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Greater Range and Longer Lifetime

26.10.2016 | Power and Electrical Engineering

VDI presents International Bionic Award of the Schauenburg Foundation

26.10.2016 | Awards Funding

3-D-printed magnets

26.10.2016 | Power and Electrical Engineering

More VideoLinks >>>