PNAS: Telomere-lengthening molecules that help cancer cells live forever and can be used as cancer treatment targets

Everything has a beginning and an end, and the same
is true for cells.
In normal human cells, telomeres at the end of chromosomes will continue to shorten as cells divide, and when telomeres are shortened to a limit, the cell will stop dividing, which is the famous "Hayflick limit"
.

However, there are exceptions to everything, unlike normal cells, cancer cells can divide indefinitely, one of the important reasons is that cancer cells have high telomerase activity, which can repair telomeres, so that cell division continues
continuously.
But it's worth mentioning that many cancer cells do not rely on telomerase to lengthen telomeres, but prevent telomere shortening through the telomere extension replacement mechanism (ALT), these cancer cells are also known as telomere extension replacement cells (ALT cells), which make up about 10%
of human tumors.

Recently, a research paper
entitled: The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted was published in the Proceedings of the National Academy of Sciences (PNAS).

The study showed that telomere repeat RNA (TERRA), an RNA molecule involved in protecting telomere length in ALT cells, could be used to fight drug-resistant ALT cells
.

Telomere repeat RNA (TERRA) is low in normal cells but much higher in ALT cells
.
There, it causes controlled DNA damage, which is then repaired in a process known as fracture-induced telomere synthesis (BITS), which ultimately increases the length
of the telomeres.
However, this does not mean that telomeres in ALT cells can withstand DNA damage in unlimited amounts, and when TERRA expression levels exceed a certain level, ALT cells also stop dividing and die
.

Dr.
Bruno Silva, the first author of the paper, said: "When the expression of TERRA increases, the damage on telomeres also increases, which will severely impair the survival of cells, and even cancer cells that are more resistant to DNA damage can no longer proliferate
.

ALT cells repair telomeres through the BITS process

In fact, in previous studies, the research team has shown that by inhibiting the expression of TERRA, it can inhibit the proliferation
of cancer cells.
For the first time, they developed a molecular drug that inhibits TERRA transcription, reducing DNA damage on telomeres in ALT cells, thereby stopping telomere extension
in these drug-resistant cancer cells.

In the study, published in PNAS, the team tried the opposite direction — to see what happens
when terra is overexpressed in ALT cells.

The research team speculated that there was likely to be a threshold for the expression of TERRA, beyond which excessive damage to telomeres would exceed the ability
of ALT cells' repair mechanisms.

This proved to be the case, and they found that when TERRA was overexpressed, the high levels of DNA damage caused greatly exceeded the repairing capacity of the DNA repair machinery, so much so that these cells needed to recruit additional telomeres to help consume the excess TERRA, resulting in multiple telomeres being lost at the same time, ultimately hindering cell division
.

Overexpression of TERRA in ALT cells

This means that TERRA could be a unique multifunctional therapeutic target: by lowering its levels, we can block telomere maintenance; And by increasing the level of TERRA, we can increase DNA damage to a point where even cancer cells cannot repair it, eventually leading to cancer cell death
.

In short, TERRA is more like a double-edged sword, which can cause huge damage
to enemies (ALT cells) no matter which side (overexpression or instigation) is used.

Overexpression of TERRA leads to ALT cell death

Currently, the research team is identifying proteins that activate or inhibit TERRA expression and plans to develop small molecule drugs that target these proteins for preclinical trials
against ALT cancer cells.