Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Protein clamps tight to telomeres to help prevent aging ... and support cancer

17.09.2010
The number of times our cells can divide is dictated by telomeres, stretches of DNA at the tips of our chromosomes. Understanding how telomeres keep our chromosomes – and by extension, our genomes – intact is an area of intense scientific focus in the fields of both aging and cancer.

Now, scientists at The Wistar Institute have published the first detailed report on the structure and function of a crucial domain in the protein known as Cdc13, which sustains telomeres by clamping to DNA and recruiting replicating enzymes to the area.

While the nature of this portion of Cdc13 had previously eluded scientists, the Wistar researchers found that two copies of the protein bind together to form what is called a “dimer,” and how that dimer physically interacts with DNA, regulating how enzymes called telomerases access and lengthen the telomeres. The study was performed using the yeast gene, however, this essential life process has changed little through evolution, and evidence suggests that the human equivalent of this protein may make a good target for future anticancer drugs. They present their findings in the journal Molecular and Cellular Biology, available online now, ahead of print.

“Cdc13 has a crucial support role in maintaining and lengthening telomeres, which are reduced in length through every round of DNA replication,” said Emmanuel Skordalakes, Ph.D., assistant professor in Wistar’s Gene Expression and Regulation Program and senior author of the study. “We know that disabling this protein in humans will most likely lead to senescence, which is of particular interest in cancer, because telomere lengthening is one of the ways cancer cells obtain their immortality."

In the present study, Skordalakes and his colleagues detail how Cdc13 serves a dual function in telomere replication. First, it keeps the cells’ natural DNA repair mechanisms from mistaking the telomere for a broken stretch of DNA, which could cause genetic mayhem if such repair proteins fuse the ends of two chromosomes together, for example. Secondly, Cdc13 recruits telomerase and related proteins to place in order to lengthen the telomeres.

When the researchers introduced mutations into Cdc13 that prevented the protein from forming a dimer, it caused the telomeres to shorten, which would hasten the demise of the yeast cells. When they created mutations that prevented Cdc13 dimers from binding to DNA, it had the effect of excessively lengthening telomeres, an act the researchers attribute to the notion that Cdc13 helps regulate the ability of DNA-replication enzymes to access telomeres. “The complex role of Cdc13 underscores the unique nature of telomeres and the fine balance between normal cell division and cancer,” said Skordalakes.

Telomeres are important to cell division because they serve as sort of a timing mechanism that can, in effect, limit the number of times a normal cell can divide. As each cell divides, it must first replicate – or copy – the DNA of its chromosomes in exacting detail.

However, the proteins in cells that make this replication possible physically cannot copy the last few base units of DNA at the tips of the chromosomes, which effectively shortens the telomere each time a chromosome is copied. Without telomeres to serve as a buffer, a chromosome could conceivably lose a functioning gene as it is copied. This natural “lifespan” of cells was first identified in the 1960s as the Hayflick Limit, named after its discoverer, Leonard Hayflick, Ph.D., then a Wistar scientist.

In 2008, the Skordalakes laboratory was the first to determine the 3-D structure of the catalytic subunit of the enzyme telomerase, which functions to tack on the short stretches of DNA at the telomeres that the cell’s main DNA-replicating enzymes miss. The act of preserving telomeres through telomerase is a hallmark of only certain cells, particularly those in developing embryos. In adults, telomerase is active in stem cells, certain immune system cells and, most notably, cancer cells.

According to Skordalakes, the discovery of the dimeric nature of Cdc13 sheds light into the core function of this protein, the recruitment of telomerase (which is also a dimer) to the telomeres. Within the Cdc13 dimer are multiple sites that can bind to DNA with varying degrees of affinity. This allows Cdc13 to straddle the DNA so that one section grips tightly to DNA, while another section – with a more relaxed grip – can bind nearer the tail end of the DNA strand and where telomerase binds. This feature of Cdc13 also assists in recruiting telomerase, summoning the enzyme into place above the telomere.

The 'weak hand' (light blue) of Cdc13 attaches to the tail end of the telomere, swinging out of the way to allow telomerase (green) to attach to and lengthen the telomeric DNA."

“You can think of Cdc13 as if it were you hanging on to the edge of a cliff, with one grip stronger than the other,” Skordalakes said. “You’re going to keep that strong hand on the cliff’s edge while your weaker hand reaches into your pocket for your phone.”

When Cdc13 interacts with telomerase, Skordalakes says, its weaker hand lets go of DNA, allowing the telomerase to access the telomere while the “strong hand” keeps the telomerase-Cdc13 complex firmly attached to the chromosome end. “It effectively serves as both a protective placeholder and a means of guiding telomerase activity,” Skordalakes said.

The Skordalakes laboratory continues to explore the complex biology of telomeres, as well as the numerous other proteins necessary for telomere lengthening to occur. Meanwhile, they are investigating the potential of small molecule inhibitors to serve as viable therapeutics against cancer by blocking telomerase and their related proteins.

Co-authors from The Wistar Institute include David W. Speicher, Ph.D., a Wistar professor, and laboratory staff Meghan Mitchell (a former research assistant under Skordalakes), Mark Mason (a graduate student under Skordalakes), and Sandy Harper (a technician under Speicher ). They were joined by Jasmine S. Smith and F. Brad Johnson, M.D., Ph.D., from the University of Pennsylvania School of Medicine’s Department of Pathology and Laboratory Medicine.

The research was supported by grants from the Pennsylvania Department of Health, The Ellison Medical Foundation, The Emerald Foundation, Inc., and the National Institute on Aging of the National Institutes of Health.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures. On the Web at www.wistar.org.

Greg Lester | EurekAlert!
Further information:
http://www.wistar.org

Further reports about: Cdc13 DNA Protein biomedical research cancer drug cell division health services stem cells

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>