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

November 29, 2012

CHAMPAIGN, lll. -- New insights into a protein complex that regulates the very tips of chromosomes could improve methods of screening anti-cancer drugs.

Led by bioengineering professor Sua Myong, the research group's findings are published in the journal Structure.

Myong's group focused on understanding the proteins that protect and regulate telomeres, segments of repeating DNA units that cap the ends of chromosomes. Telomeres protect the important gene-coding sections of DNA from loss or damage, the genetic equivalent of aglets - the covering at the tips of shoelaces that keep the ends of the laces from unraveling or fraying.

Telomeres play an important role in cell aging and death, since each time a cell divides, a little bit is lost from the end of the telomere. Thus, cell biologists postulate that telomere length can determine the lifespan of a cell. Cancer cells, however, have a way to get around this limitation: An enzyme called telomerase that adds length to telomeres is highly active in cancer cells. This allows cancer cells to divide in perpetuity, running amok through tissues and systems.

"Cancer researchers want to get a hold of this problem, control this indefinite lengthening of the telomeres," said Myong, who also is affiliated with the Institute for Genomic Biology at the U. of I. "A lot of the anti-cancer drugs are targeted directly to these telomeres so that they can inhibit telomerase activity. The proteins we study regulate the activity of telomerase."

Using a technique developed at Illinois that allows researchers to watch single molecules interact in real time, Myong's group determined how two proteins called POT-1 and TTP-1 bind to the telomere. POT-1 protects the fragile telomere ends from being attacked by other regulatory proteins that might mistake the end for a broken or damaged area of DNA. When POT-1 and TTP-1 work together in a complex, they promote telomerase activity, an interesting target for cancer researchers.

The group found that on its own, POT-1 binds to the folded-up telomere in distinct steps at particular points in the telomere's DNA sequence, unfolding the telomere in a stepwise manner. However, the POT-1/TTP-1 complex surprised the researchers by binding, then freely sliding back and forth along the telomere end.

"Instead of stepwise binding, what we saw was a mobile protein complex, a dynamic sliding motion," Myong said. "Somehow it was as if the static binding activity of POT-1 is completely lost - the protein complex just slid back and forth. We were able to reproduce the data and confirm it with many different tail lengths of the telomeric DNA and we know now that the contact between POT-1 and the telomere is somehow altered when the partner protein comes and binds."

Next, the researchers will add telomerase and see how the sliding activity of the POT-1/TTP-1 complex affects telomerase activity. Myong postulates that the sliding may promote telomerase activity - and thus telomere lengthening - by making the end of the telomere accessible for the telomerase enzyme to bind.

"We are excited about the possibility that this kind of mobility can increase the telomerase extension activity," Myong said. "It's somehow engaging the enzyme so that it can stay bound to the DNA longer. So it must involve a direct interaction."

Ultimately, understanding the POT-1/TTP-1 complex gives drug developers a new target for anti-cancer drugs, and the assay Myong's group used to monitor the complex could offer a venue for evaluating telomere-targeting drugs.

"We want to extend our a basic science knowledge in telomere biology into causes of cancer and we hope that our assay can be useful for telomere-targeted drug screening," Myong said.
-end-
The American Cancer Society and the Human Frontier Science Research Program supported this work.

Editor's note: To reach Sua Myong, call 217-244-6703; email smyong@illinois.edu. The paper, "POT1-TPP1 Regulates Telomeric Overhang Structural Dynamics'" is available online.

University of Illinois at Urbana-Champaign

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.