Novel technique reveals dynamics of telomere DNA structure

January 17, 2013

Biomedical researchers studying aging and cancer are intensely interested in telomeres, the protective caps on the ends of chromosomes. In a new study, scientists at UC Santa Cruz used a novel technique to reveal structural and mechanical properties of telomeres that could help guide the development of new anti-cancer drugs.

Telomeres are long, at the ends of chromosomes that serve a protective function analogous to that of the plastic tips on shoelaces. As cells divide, their telomeres get progressively shorter, until eventually the cells stop dividing. Telomeres can grow longer, however, through the action of an enzyme called telomerase, which is especially active in cells that need to keep dividing indefinitely, such as stem cells. Researchers have also found that most tumor cells show high telomerase activity.

Michael Stone, an assistant professor of chemistry and biochemistry at UC Santa Cruz, said his lab is particularly interested in the folding and unfolding of a at the tail end of the telomere, known as a G-quadruplex, because it plays a key role in regulating .

"Most use telomerase as one mechanism to maintain uncontrolled growth, so it is an important target for anti-," Stone said. "The G-quadruplex structures of telomere DNA inhibit the function of the , so we wanted to understand the mechanical stability of this structure."

Xi Long, a graduate student in Stone's lab, led the project, which involved integrating two techniques to manipulate and monitor single DNA molecules during the unfolding of the G-quadruplex structure. A "magnetic tweezers" system was used to stretch the , while a fluorescence was used to monitor small-scale structural changes in the DNA. The results, published in , showed that a relatively small structural displacement causes the G-quadruplex to unfold.

"Unlike other DNA structures, the G-quadruplex structure is fairly brittle. It takes very little perturbation to make the whole thing fall apart," Stone said. "We also found that the unfolded state has a highly compacted conformation, which tells us that it still has interactions that favor the folding reaction."

These findings have implications for understanding the molecular mechanisms of telomere-associated proteins and enzymes involved in the unfolding reaction, as well as for rational design of anti-cancer drugs, Stone said. Small molecules that bind to and stabilize telomere DNA G-quadruplexes have shown promise as anti-.

The integration of fluorescence measurements and magnetic tweezers is a powerful method for monitoring DNA structural dynamics, and as biophysical techniques go, it is not hard to implement, Stone said. His lab worked with DNA molecules containing the G-quadruplex sequence from human telomere DNA, attaching one end of the DNA to a glass slide and the other end to a tiny magnetic bead. A magnet held above the sample pulled on the bead, exerting a stretching force on the DNA molecule that varied according to how close the magnet was to the sample.

At the same time, the researchers used a fluorescence technique called single-molecule FRET (Förster resonance energy transfer) to monitor small-scale structural changes in the DNA. "FRET can be thought of as a molecular ruler," Stone said. As energy from one fluorescent dye molecule is transferred to a second dye molecule, the efficiency of the energy transfer can be measured in real time. The dye molecules can be coupled directly to the DNA molecule at specific sites, allowing researchers to monitor the molecular dynamics of the system as it is being manipulated by the magnetic tweezers.

"You don't have to be a specialist to use this technique, so it can be easily transferred to other labs and broadly employed in these kinds of studies," Stone said.

Explore further: Proteins that work at the ends of DNA could provide cancer insight

Related Stories

Proteins that work at the ends of DNA could provide cancer insight

November 29, 2012
(Medical Xpress)—New insights into a protein complex that regulates the very tips of chromosomes could improve methods of screening anti-cancer drugs.

Scientists capture single cancer molecules at work

December 8, 2011
Researchers have revealed how a molecule called telomerase contributes to the control of the integrity of our genetic code, and when it is involved in the deregulation of the code, its important role in the development of ...

Alternate ending -- living on without telomerase

November 3, 2011
Scientists of the German Cancer Research Center have discovered an alternative mechanism for the extension of the telomere repeat sequence by DNA repair enzymes.

Research reveals how cancer-driving enzyme works

May 6, 2011
Cancer researchers at UT Southwestern Medical Center are helping unlock the cellular-level function of the telomerase enzyme, which is linked to the disease's growth.

Recommended for you

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.