Michigan researchers’ telomerase process discovery could yield universal cancer therapies

By investigating telomerase, an enzyme that adds DNA sequence repeats, researchers at the University of Michigan Comprehensive Cancer Center have uncovered a step in that process that stops cells from becoming cancerous

Amy Swinderman
ANN ARBOR, Mich.—By investigating telomerase, an enzyme that adds DNA sequence repeats, researchers at the University of Michigan Comprehensive Cancer Center have uncovered a step in that process that stops cells from becoming cancerous. Although the researchers stress that their findings are based on "basic science" and are still preliminary, they are predicting that their discovery could be used as the basis for developing new cancer therapies.

Publishing their efforts in the Feb. 16 edition of Developmental Cell, the research team, led by senior author Dr. Ming Lei, assistant professor of biological chemistry at the University of Michigan Medical School, probed the role of telomerase in the growth of cancer. It all starts with telomerase, which affects the telomeres, or caps, at the end of the chromosome. Telomeres shorten over time, but telomerase prevents this from happening. If cancer is triggered in the cell, the presence of telomerase leads to the growth of the cancer.

According to previously published research, telomerase is kept in control by the protein TRF1, which keeps the telomeres operating correctly. But another protein, Fbx4, can bind to TRF1 and degrade it, causing the telomeres to lengthen.

In this study, the Michigan researchers discovered a third protein, TIN2, which can step in and override Fbx4 by binding to TRF1 first and preventing Fbx4 from attaching to it. The researchers found that the location in the molecule where Fbx4 binds to TRF1 overlaps with where TIN2 binds to TRF1. Where both Fbx4 and TIN2 are present, the TIN2 wins out and binds to the TRF1 first. This blocks Fbx4 from binding to the TRF1, thereby stabilizing TRF1 and keeping the telomere length in control.

According to the researchers, their finding paves the way for developing a drug that acts like TIN2. What's more, such a drug could be used to develop universal treatments for cancer, as telomerase is involved in all forms of the disease. This is in contrast to current molecularly targeted therapies, which address a pathway or gene that is involved in only specific types of cancer.

"In 90 percent of cancers, no matter what caused the cancer to form, it needs telomerase activity to maintain the cell. Without telomerase, the cell will die. Our work is key to understanding a detailed mechanism for how these molecules interact and how to design a drug to block Fbx4," Lei says. "Most cells in the human body have no telomerase activity, but in most cancer cells, telomerase activity is reactivated again. This is a very attractive and useful approach to limiting cancer cell growth because cancer cells depend heavily on that."

Next, the researchers will look at peptides that mimic TIN2's binding to TRF1, in order to block Fbx4. The work is still in preliminary stages and no new therapies are being tested in patients, Lei says, and the researchers do not yet have any commercial partners in mind to begin that process.

"We have a really long way to go," Lei stresses. "Our science is very basic science, and will become interesting only when other companies come in and take over. We are exploring the possibility of that. For now, we're happy to bring up some new ideas when it comes to cancer treatments and bring people together to consider new angles."

The study, Structural Basis of Selective Ubiquitination of TRF1 by SCF(Fbx4), was funded by the National Institutes of Health, an American Cancer Society Research Scholar grant, a Sidney Kimmel Scholar Award, the National Cancer Institute, the National Institute of General Medical Science, and the U.S. Department of Energy's Office of Basic Energy Sciences.
 

Amy Swinderman

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