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 "Make two out of one" - Division of Artificial Cells
19.02.2020 | Max-Planck-Institut für Kolloid- und Grenzflächenforschung

nachricht Sweet beaks: What Galapagos finches and marine bacteria have in common
19.02.2020 | Max-Planck-Institut für Marine Mikrobiologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A step towards controlling spin-dependent petahertz electronics by material defects

The operational speed of semiconductors in various electronic and optoelectronic devices is limited to several gigahertz (a billion oscillations per second). This constrains the upper limit of the operational speed of computing. Now researchers from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg, Germany, and the Indian Institute of Technology in Bombay have explained how these processes can be sped up through the use of light waves and defected solid materials.

Light waves perform several hundred trillion oscillations per second. Hence, it is natural to envision employing light oscillations to drive the electronic...

Im Focus: Freiburg researcher investigate the origins of surface texture

Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.

Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...

Im Focus: Skyrmions like it hot: Spin structures are controllable even at high temperatures

Investigation of the temperature dependence of the skyrmion Hall effect reveals further insights into possible new data storage devices

The joint research project of Johannes Gutenberg University Mainz (JGU) and the Massachusetts Institute of Technology (MIT) that had previously demonstrated...

Im Focus: Making the internet more energy efficient through systemic optimization

Researchers at Chalmers University of Technology, Sweden, recently completed a 5-year research project looking at how to make fibre optic communications systems more energy efficient. Among their proposals are smart, error-correcting data chip circuits, which they refined to be 10 times less energy consumptive. The project has yielded several scientific articles, in publications including Nature Communications.

Streaming films and music, scrolling through social media, and using cloud-based storage services are everyday activities now.

Im Focus: New synthesis methods enhance 3D chemical space for drug discovery

After helping develop a new approach for organic synthesis -- carbon-hydrogen functionalization -- scientists at Emory University are now showing how this approach may apply to drug discovery. Nature Catalysis published their most recent work -- a streamlined process for making a three-dimensional scaffold of keen interest to the pharmaceutical industry.

"Our tools open up whole new chemical space for potential drug targets," says Huw Davies, Emory professor of organic chemistry and senior author of the paper.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

70th Lindau Nobel Laureate Meeting: Around 70 Laureates set to meet with young scientists from approx. 100 countries

12.02.2020 | Event News

11th Advanced Battery Power Conference, March 24-25, 2020 in Münster/Germany

16.01.2020 | Event News

Laser Colloquium Hydrogen LKH2: fast and reliable fuel cell manufacturing

15.01.2020 | Event News

 
Latest News

"Make two out of one" - Division of Artificial Cells

19.02.2020 | Life Sciences

High-Performance Computing Center of the University of Stuttgart Receives new Supercomuter "Hawk"

19.02.2020 | Information Technology

A step towards controlling spin-dependent petahertz electronics by material defects

19.02.2020 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>