Navigation Links
Novel technique reveals dynamics of telomere DNA structure

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, repetitive DNA sequences 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 DNA structure at the tail end of the telomere, known as a G-quadruplex, because it plays a key role in regulating telomerase activity.

"Most cancer cells use telomerase as one mechanism to maintain uncontrolled growth, so it is an important target for anti-cancer therapeutics," Stone said. "The G-quadruplex structures of telomere DNA inhibit the function of the telomerase enzyme, 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 DNA molecule, while a fluorescence microscopy technique was used to monitor small-scale structural changes in the DNA. The results, published in Nucleic Acids Research, 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-cancer drugs.

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 (Frster 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.

Contact: Tim Stephens
University of California - Santa Cruz

Related biology news :

1. Researchers discover novel therapy for Crohns disease
2. New clinical trial explores novel noninvasive colon cancer screening test
3. Notre Dame researchers using novel method to combat malaria drug resistance
4. Unique adaptations to a symbiotic lifestyle reveal novel targets for aphid insecticides
5. Key proteins newly discovered form and function may provide novel cancer treatment target
6. Novel discovery by NUS scientists paves the way for more effective treatment of cancers
7. London researchers discover novel mechanism involved in key immune response
8. Mexican rock heroes trial novel green trading system
9. VTT and GE Healthcare developing novel biomarkers to predict Alzheimers disease
10. Cleveland Clinic researchers receive $5 million grant to discover novel pathways to heart disease
11. Novel nano-structures to realize hydrogens energy potential
Post Your Comments:
(Date:11/19/2015)... 2015  Although some 350 companies are actively involved ... few companies, according to Kalorama Information. These include Roche Diagnostics, ... market share of the 6.1 billion-dollar molecular testing market, ... for Molecular Diagnostic s .    ... controlled by one company and only a handful of ...
(Date:11/17/2015)... , Nov. 17, 2015  Vigilant Solutions announces ... joined its Board of Directors. --> ... after recently retiring from the partnership at TPG Capital, ... companies with over $140 Billion in revenue.  He founded ... across all the TPG companies, from 1997 to 2013.  ...
(Date:11/12/2015)... 11, 2015   Growing need for low-cost, ... has been paving the way for use of ... discrete analytes in clinical, agricultural, environmental, food and ... used in medical applications, however, their adoption is ... to continuous emphasis on improving product quality and ...
Breaking Biology News(10 mins):
(Date:11/25/2015)... November 26, 2015 ... Market 2016 - 2020 report analyzes that automating ... and quality in long-term samples, minimizing manual errors, ... Automation minimizes manual errors such as mislabeling or ... Further, it plays a vital role in blood ...
(Date:11/25/2015)... Studies reveal the differences in ... pave the way for more effective treatment for one of ...   --> --> Gum ... in cats, yet relatively little was understood about the bacteria ... been conducted by researchers from the WALTHAM Centre for Pet ...
(Date:11/25/2015)... QUEBEC CITY , Nov. 25, 2015 /PRNewswire/ ... "Company"), affirms that its business and prospects remain ... , Zoptrex™ (zoptarelin doxorubicin) recently received DSMB ... program to completion following review of the final ... met Phase 2 Primary Endpoint in men with ...
(Date:11/25/2015)... , November 25, 2015 ... Report is a professional and in-depth study on ...      (Logo: ) , ... the industry including definitions, classifications, applications and industry ... for the international markets including development trends, competitive ...
Breaking Biology Technology: