Unreliable telomeres

St. Petersburg State University Press Service 

A number of processes in the human body – from cell aging to the appearance of malignant tumors – depend on telomeres, special structures located at the ends of chromosomes. It is generally believed that telomeric repeats (DNA sequences underlying telomeres) protect the ends of chromosomes from degradation. However, studies conducted by scientists at St. Petersburg State University have shown that these are some of the most unstable sequences in the genome. The discovery, which will help in the treatment of the most aggressive forms of cancer and prolong human life, was reported in November by the journal Cell Reports.

The stability of the human genome is largely determined by telomeres. If they were not there, the cell's defense systems would take the ends of chromosomes for a special type of damage – double-stranded DNA breaks. The cell would try to repair the damage, creating even bigger problems – rearrangements and loss of chromosomes. The presence of telomeres protects the ends of chromosomes, but with each cell division, the chromosomes double and the telomeres shorten. However, the body uses this "disadvantage" for its own purposes: the size of telomeres serves as a limiter of the number of divisions. That is why ordinary (somatic) cells can divide only about 50 times, while embryonic and stem cells can divide indefinitely. This is due to the presence of a special enzyme in them – telomerase, which completes (lengthens) telomeres. It is important that it is the launch of this enzyme that allows cancer cells to divide indefinitely, that is, it provokes uncontrolled growth of a cancerous tumor.

However, despite the fact that telomeric repeats protect the ends of chromosomes from shortening, degradation and rearrangements, it turned out that they are highly unstable: telomeric repeats placed inside chromosomes can cause chromosomal rearrangements and mutagenesis (changes in DNA). St. Petersburg State University scientists together with colleagues from Tufts University (USA) have developed a model yeast system of S. cerevisiae, which allowed us to establish that telomeric tracts can also spontaneously lengthen with high frequency. The research results are easily projected onto humans, since the mechanisms for maintaining telomere length are very conservative from the simplest to higher organisms.

Having studied the mechanism of telomere repeat elongation in the model system, the researchers found that it is in many ways similar to the process of alternative telomere elongation, which allows them to grow without telomerase. This mechanism is used by about 15% of cancerous tumors. The first (main) author of the article in Cell Reports, senior researcher at the Laboratory of Amyloid Biology of St. Petersburg State University Anna Aksenova notes that these are the most aggressive cancers that are practically untreatable due to the rapid variability of the tumor genome, for example osteosarcoma, neuroblastoma, brain tumors, and, according to new data, this group also includes some types of blood cancer.

"Scientists have long known the role that telomerase plays in the development of cancerous tumors, and many inhibitors of this enzyme have already been developed. However, very often when using these drugs, the same mechanism of alternative telomere elongation is activated – that is, we kill telomerase, and cancer cells continue to live and divide," explains Anna Aksenova. Until now, many details of the most important mechanism of alternative telomere elongation remain unexplored. A model system created by scientists from St. Petersburg State University and Tufts University allows us to study this process. Also, the data obtained shed light on the behavior of intra-chromosomal telomeric repeats, which are present in the genome along with the usual terminal ones. It is worth noting that the instability of intra-chromosomal telomeric repeats is associated with a number of diseases, including cancer.

In the future, the model system developed by the researchers can help oncologists not only predict the course of the disease in patients, but also test the effectiveness of drugs, as well as identify a predisposition to cancer in healthy people. In addition, this study opens up prospects for scientists in the fight against aging. "The prolongation of human life will largely depend on solving the problem of terminal replication of chromosomes and the structural integrity of telomeres. By finding a way to protect the ends of chromosomes from shortening, rearrangement and recombination, we will defeat aging," Anna Aksenova is sure.

The full text of the article "Expansion of interstitial telomeric sequences in yeast S. cerevisiae" can be found on the website of the journal Cell Reports (Aksenova et al., Switch to Standard View Expansion of Interstitial Telomeric Sequences in Yeast).

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08.12.2015