Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Telomerase enzyme structure provides significant new target for anti-cancer therapies

15.11.2007
Findings may also provide insights into normal aging

Inappropriate activation of a single enzyme, telomerase, is associated with the uncontrollable proliferation of cells seen in as many as 90 percent of all of human cancers. Since the mid-1990s, when telomerase was first identified in human tumors, scientists have eyed the enzyme as an ideal target for developing broadly effective anti-cancer drugs.

Now, researchers working at The Wistar Institute have brought this goal closer by deciphering the three-dimensional structure of a domain, or region, of the telomerase molecule essential for the activity of the enzyme. The findings, published November 13 in the journal Structure, may help scientists develop strategies to design the first direct inhibitors of telomerase.

Telomerase also has been shown to play a central role in normal aging, and the new study may shed light on that vital life process as well. The potential for creating new cancer treatments, however, is the most important immediate implication of the study.

... more about:
»Cancer »Telomerase »anti-cancer »enzyme »structure

“Knowing the physical structure of this complex will give pharmaceutical companies a direct target for designing drugs that disrupt a mechanism that telomerase uses to assemble itself,” says Emmanuel Skordalakes, Ph.D., an assistant professor in the Gene Expression and Regulation Program at Wistar and senior author on the study. “Such drugs could well have significant anti-cancer activity.”

Telomerase is essential for normal cell division and survival, and has been associated with aging and cancer. In humans, the usual role of telomerase is to add multiple repeats of a short length of DNA to the ends of chromosomes, known as telomeres, thus preventing damage and the loss of genetic information during DNA replication. It performs this critical service in developing embryos and in a few specialized cell lines, including stem cells.

In normal adult cells, however, telomerase is switched off almost entirely to prevent the dangers of runaway cell proliferation. This lack of telomerase activity is also associated with normal aging and underlies a seminal observation known as the Hayflick limit. At Wistar in the 1960s, Leonard Hayflick, Ph.D., noted that cells in culture divide only about 50 times before dying. Later, scientists tied this effect to the shortening of telomeres with each cell division when telomerase is no longer active in the cell.

Cancer cells, however, often regain the ability to produce telomerase, permitting them to replicate indefinitely. Though scientists have sought ways to inhibit this enzyme, a lack of detailed information on the enzyme’s structure has hindered progress.

Prior studies have shown that telomerase is made up of multiple protein components and a stretch of RNA that is used as a template to create the short DNA repeats that are added to the ends of chromosomes. In order for telomerase to function, the RNA and protein components of telomerase must interact to form a stable complex capable of DNA replication. This interaction occurs mainly on the so-called TRBD domain, which plays an essential role in complex formation and full assembly of the enzyme.

“Studies show if you delete the TRBD domain from telomerase, the enzyme is inactive because it can no longer assemble with RNA,” Skordalakes says. “Without the RNA, the enzyme can no longer replicate telomeres.”

To get a clear view of this interaction, Skordalakes and co-workers obtained the three-dimensional structure of TRBD using X-ray crystallography, a technique that analyzes the diffraction patterns of X-rays beamed at crystals of a molecule to determine the molecule’s atomic structure.

Their studies reveal that the TRBD domain is shaped like a boomerang, with a structural organization that leads to the formation of a narrow well-defined pocket on the surface of the protein that enables the enzyme to bind the single-stranded RNA used as a template for the DNA repeats.

A second RNA-binding site is formed by a large cavity that serves as an extension of the single-strandedRNA-binding pocket. The extent of these RNA interactions indicates the important role of this domain in stabilizing the complex, Skordalakes says.

Franklin Hoke | EurekAlert!
Further information:
http://www.wistar.org

Further reports about: Cancer Telomerase anti-cancer enzyme structure

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

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

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>