Live longer and die of cancer?

Chromosomal tails as a defense against cancer

Kirill Stasevich, Science and Life (nkj.ru )

Chromosomal ends-tails are called telomeres, and we hear about them very often. Telomeres are one of the indicators of cellular aging: the older the cell, the shorter its telomeres. The fact is that when a cell divides, it doubles each of its chromosomes so that each of the two daughter cells gets a copy. But proteins that are engaged in replication (DNA doubling) are arranged in such a way that they cannot read and copy the DNA strand to the end. That is, at the end of each chromosomal DNA there is a piece that is not copied into the new DNA, so that the new DNA turns out to be slightly shorter than the old one.

If there were genes encoding proteins or some other important DNA sequences at the end of the chromosome, then trouble would happen: they would not exist at all in the shortened chromosome, or they would be damaged. But at the ends of DNA there are meaningless telomeres that don't encode anything – they just help cells divide without harming the genome. However, telomeres are not infinite. When they are shortened to a certain size, the cell can no longer divide. In other words, the old cell is the one that has exhausted the limit of divisions. Then she can only die.

But there are cells that can divide for a very, very long time – stem cells. They have the enzyme telomerase, which lengthens telomeres. Stem cells gradually turn into specialized cells (skin cells, muscle cells, liver, etc.), and now in specialized cells telomerase no longer works. If a specialized cell has died, it can only be replaced with the help of stem cells. But why wouldn't telomerase also work in ordinary cells that could continue to live and divide?

Telomerase works not only in stem cells. We have another cell capable of endless division – cancer cells. In a recent article in eLife (Schmutz et al., TINF2 is a haploinsufficient tumor suppressor that limits telomere length), employees Rockefeller University and the University of Nijmegen write that telomeres are a safeguard against malignant degeneration. The fact is that while a cell lives and divides, various mutations accumulate in its DNA. There are special proteins in the cell that correct them, but some mutations still remain. And gradually they accumulate so much that they already significantly affect how the cell does its job. An aged cell no longer benefits as much as it harms. Moreover, among the remaining mutations, there are often those that make the cell malignant. Now she definitely does not do any useful work and does not even pay attention to the surrounding normal cells – now she just divides, forming a tumor.

And here telomeres turn out to be very useful. Even if the cell has lost its own intracellular settings, even if now its internal signals compel it to divide non-stop, but it will be able to share until the telomeres are shortened to the prescribed limit. When it shortens, the self-destruct program will turn on in the cell.

However, malignant tumors still appear. However, according to the authors of the work, the tumor can count on success only if it can activate telomerase. Indeed, most of the malignancies that are detected during clinical examination exist with telomerase enabled. To turn it on, mutations are needed again. The longer a cell lives, the greater the probability of mutations. Imagine that the telomeres of a cell initially turned out to be longer than usual. Then she will live longer, she is more likely to have a mutation in the telomerase gene, which will turn on and begin to build up telomeres, playing in favor of cancer.

Telomerase does not exist by itself, its activity depends on other proteins. In their article, the researchers talk about one such protein called TIN2. It has been known for a relatively long time that mutations in the TIN2 gene seem to remove the fuse from telomerase, which begins to actively lengthen chromosomal tails. This time it was possible to show that the initial telomere length with which the cell enters, so to speak, into mature life depends on TIN2.

The authors analyzed the genes of several families predisposed to cancer. They managed to identify characteristic mutations in the TIN2 gene, passing from generation to generation. In the experimental cells that were injected with this mutation, the telomeres turned out to be much longer than they should be. Moreover, there were no other problems with DNA initially, the genome was stable, telomerase remained disabled. The only anomaly turned out to be too long telomeres, which made it possible to live longer.

The following sequence of events turns out: due to a mutation in the TIN2 protein, it ceases to properly control telomerase, which awards chromosomes with too long tails in the early stages of development. Then telomerase falls asleep, and the cells live and work, from time to time dividing and accumulating mutations (which, incidentally, also occur when DNA is doubled). Due to the extended life span, more mutations appear in cells, including malignant ones, and these mutations have more chances to finally turn the cell into a cancerous one (in particular, they are more likely to wake up telomerase and finally solve the problem with shortening telomeres).

It turns out that short telomeres serve as safeguards against cancer. If the chromosome ends were longer, cancer would be much more common and would probably be even more diverse. However, although the hypothesis of telomeric protection against cancer has been discussed for a long time, not everyone agrees with it. Although this work offers additional (albeit indirect) arguments in its favor, the debate among experts about the evolutionary significance of telomeres is unlikely to subside so soon.

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