There is no silver lining

With age, telomeres located at the ends of chromosomes become shorter. This process has long been regarded as an undesirable side effect of aging, but a recent study has shown that it can be useful for humans.

Telomeres protect genetic material. With each cell division, they shorten, and when the length reserve ends, the cell no longer divides and dies.

Human telomeres (green) at the ends of chromosomes (blue).

The results of a new study by Titia de Lange and her colleagues from Rockefeller University, USA, have provided new evidence that shortening telomeres helps prevent cancer in humans, probably due to the ability to stop cell division. The results were obtained by analyzing mutations in families with a burdened hereditary history, and they provide an answer to a long-standing question about the relationship between telomeres and cancer.

A fundamental contradiction

In stem cells, including those that produce eggs and sperm, telomere length is maintained by telomerase, an enzyme that adds telomeric DNA to the ends of chromosomes. But telomerase is absent in mature human cells, so the telomeres on their chromosomes are shortened. This gradual decrease in telomere length limits the number of divisions of normal human cells to about 50.

The hypothesis that telomere shortening may be part of the body's defense against cancer was first put forward several decades ago. Scientists have suggested that after 50-fold division of a tumor cell at an early stage, the depletion of the telomere reserve blocks the further development of cancer. Only those cancers that manage to activate telomerase can overcome this barrier.

Clinical observations seem to have confirmed this hypothesis. Most clinically manifested cancers have reactivated telomerase, often as a result of mutations. Moreover, experiments on mice have shown that shortening telomeres can really protect against cancer. However, evidence for the suppressive role of telomere depletion on tumor growth in humans has remained inconclusive over the past two decades.

Solving a long-standing problem

Tumor suppression associated with short telomeres can only occur if a person was born with telomeres of the correct length. If they are too long, the telomere reserve will not be exhausted in time to stop the development of cancer. Longer telomeres will give cancer cells additional division cycles during which mutations can penetrate the genetic code, including mutations that activate telomerase.

For decades, de Lange's group has been studying the complex process by which telomeres are regulated. They and other scientists have identified a set of proteins that can limit the length of telomeres in cell lines, including the TIN2 protein. When TIN2 is inhibited, telomerase accumulates and excessively lengthens telomeres. But it was not known whether TIN2 also regulates telomere length at birth.

The impasse with telomeric tumor suppression persisted until doctors at Radboud University Medical Center in the Netherlands contacted de Lange about several cancer-prone families. The doctors found that in these families there were mutations in the TINF2 gene encoding the TIN2 protein, which plays an important role in controlling telomere length. That's when they asked de Lange and her colleagues to step in.

The team used CRISPR gene editing technology to create cells with exactly the same mutations as in Dutch families, and examined the resulting mutant cells. She found that mutant cells are characterized by fully functional telomeres and the absence of genomic instability. In fact, these were normal healthy cells.

But there was still one problem: their telomeres became too long. The telomeres of the cells taken from the patients were also unusually long, well above the 99th percentile.

The data showed that if a person was born with long telomeres, he has a high risk of cancer. That is, the loss of the suppressor effect of short telomeres on tumors in families from the Netherlands led to breast cancer, colorectal cancer, melanoma and thyroid cancer. These cancers were usually blocked by telomere shortening. A wide range of cancers in these people shows the power of the mechanism of telomere suppression of tumors.

Article I.Schmutz et al. TINF2 is a haploinsufficient tumor suppressor that limits telomere length published in the journal eLife.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of The Rockefeller University: Telomere shortening protects against cancer.