Shortening Telomeres Provide Protection Against Cancer

Shortening Telomeres Provide Protection Against Cancer
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Telomere shortening, known to be a side-effect of human aging, has long been viewed in a negative light. Now, research from the lab of Titia de Lange, Ph.D., at Rockefeller University shows this natural shortening of the tips of human chromosomes can actually have a health benefit

The results of the de Lange lab’s research, published in eLife, are the first to present evidence that the shortening of telomeres can help prevent the development of cancer in humans, likely due to the resultant curtailment of cell division.

The idea that telomere shortening may help protect people against cancer has existed for decades. In stem cells, including those that generate eggs and sperm, telomeres are maintained by telomerase, an enzyme that adds telomeric DNA to the ends of chromosomes. But telomerase is not found in normal human cells which is why telomeres shorten with each cell division, limiting these divisions to about 50 in normal human cells. This depletion would also curtail the ability of cancer cells to divide blocking its development, with only those cancers able to activate telomerase able to circumvent this limitation.

As de Lang notes, clinical observations have supported this hypothesis: “”Most clinically detectable cancers have re-activated telomerase, often through mutations.” Previous studies in mice have also showed the cancer-protective properties of shortening telomeres, however the telomere tumor suppressor system has remained a mystery, and its existence in humans has been questioned over the past 20 years.

Now the research of the de Lange lab has uncovered the key, revealing that the telomere suppressor pathway only works in humans who are born with telomeres of the right length. Telomere that are too long would not be run out of their reserves in time to stop the cell division progression of cancer—the longer telomeres provide a greater number of cell divisions that can eventually allow mutations to creep into the genetic code, including mutations that activate telomerase.

The de Lange lab has spent decades studying the complex process telomere regulation. Among the set of proteins that can limit telomere length in cultured human cells, identified by de Lange and other researchers, is one called TIN2. When TIN2 is inhibited, telomerase runs wild and over-elongates telomeres. It was not known, however, whether TIN2 also played a role in regulating the length of telomeres at birth.

A breakthrough came when physicians at the Radboud University Medical Center in Holland contacted de Lange about several cancer-prone families that showed mutations in TINF2 seeking answers. Isabelle Schmutz, Ph.D., a postdoc working in the de Lange lab used CRISPR to engineer cells with precisely the same mutations as those seen in the Dutch families and examined the resulting mutant cells. She found that the mutant cells had fully functional telomeres and no genomic instability.

But there was one thing wrong with the cells. “Their telomeres became too long, ” de Lange says.  Similarly, the Dutch patient’s telomeres were unusually long—well above the 99th percentile.

“The data show that if you’re born with long telomeres, you are at greater risk of getting cancer,” says de Lange. “We are seeing how the loss of the telomere tumor suppressor pathway in these families leads to breast cancer, colorectal cancer, melanoma, and thyroid cancers. These cancers would normally have been blocked by telomere shortening. The broad spectrum of cancers in these families shows the power of the telomere tumor suppressor pathway.”