Oglionucleotides that Interfere in Telomerase Activity Without Killing Cells

It seems reasonable to think that sabotaging the lengthening of telomeres might prove to be the basis for a universal cancer therapy, capable of shutting down all cancers. Unfettered telomere lengthening is required by all cancers in order to permit rampant replication and growth. Without that capability, the cancer will wither. Telomere length is a part of the mechanism limiting cell replication; cells lose a little of that length with each cell division, and short telomeres force senescence or self-destruction via programmed cell death. In normal tissues only stem cells use telomerase in order to maintain lengthy telomeres. Cancer cells abuse telomerase and the normally silent alternative lengthening of telomeres (ALT) mechanisms in order to bypass the usual restrictions on cell replication. Given this, we should all be most interested in any signs of a way to safely suppress telomerase, as in the research reported here.

The ends of chromosomes are covered with a kind of safety caps - telomeres. These are compact DNA sequences that stabilize chromatin structure. With each cell division telomeres become shorter, and the older a cell, the shorter are the telomeres of its chromosomes. However, certain types of cells (e.g. germ cells, stem cells, and lymphocytes) have an active immortality enzyme called telomerase. It compensates for the shortening of telomeres and allows the cells to divide practically endlessly. The highest telomerase activity is observed in cancer cells - this is one of the factors that makes them malignant.

Biochemists have now demonstrated that the activity of telomerase may be reduced using specific oligonucleotides (short DNA fragments). "We wanted to find out whether the oligonucleotides in charge of splicing shift (splicing is the process of cutting and reattaching of mRNA segments) are able to slow down the activity of telomerase. We studied it on the example of human T-lymphocytes. As a result, we managed to find an oligonucleotide able to actively suppress telomerase and slow down cell proliferation without killing the cells."

The main way of influencing the activity of telomerase is associated with the inducing of alternative splicing of its mRNA. As a result of this process several non-active protein forms are synthesized in a cell. The biochemists affected the alternative splicing using three types of oligonucleotides specific for different regulatory areas of telomerase mRNA. They were injected into human T-lymphocyte cells, and the activity of telomerase was measured after one day. It turned out that individual oligonucleotides did not influence the enzyme considerably, but the combination had a profound effect: the activity of telomerase reduced to 50% within the first 24 hours, to 18% - within the second, and to 10% - within the third.

Link: https://www.eurekalert.org/pub_releases/2019-02/ru-rbf021119.php


I vaguely remember that there were cancers that don't restore the telomeres very well and have a very high mutation rate due to stitching dangling DNA chunks when the telomeres are depleted..

Posted by: cuberat at February 14th, 2019 8:07 AM

Getting the oligonucleotide into the target cell by " injection " must be enormously labour intensive. A vastly easier method would be to use exosomes loaded with the oligonucleotides to do the work for you.

Posted by: JLH at February 14th, 2019 12:54 PM
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