Cheat telomerase
Telomerase is a reverse transcriptase that uses an RNA template to synthesize telomeres. When telomeres are damaged, the cell often recognizes unprotected DNA as a break in the double chain and tries to "repair" it.
Restoration of the exposed ends of DNA, which are not actually broken, leads to abnormal fusion of chromosomes. This can lead to cancer. Fortunately, cells have a mechanism for checking DNA damage in the next cell cycle, and if the presence of a defect is confirmed, apoptosis occurs – programmed cell death.
With each division, the telomeres gradually shorten. Guanine– a nitrogenous base found in large quantities in telomerase, tends to hydrolyze. After the end of the embryonic development period, most cells turn off telomerase, but there are a few important exceptions. For example, stem cells that constantly generate new sperm, or some long-lived memory B-lymphocytes keep telomerase active. Another exception is tumor cells – about 90% of them reactivate telomerase.
It would be logical to treat the tumor by blocking telomerase again. Unfortunately, this strategy was not successful, because in order for cancer cells to exhaust telomeres, it takes a lot of time, which they do not waste, continuing to divide and using the so-called alternative telomere elongation.
A group of researchers led by Derek Taylor proposed another strategy to fight cancer: using telomerase expression in cancer cells as a Trojan horse by delivering "dummy" nucleotides that will build defective telomeres. These telomeres will trigger apoptosis.
Pyrimidine analogues successfully incorporated into telomerase RNA. Source: article in the journal Cell Reports.
The researchers demonstrated that a fluorinated pyrimidine analog (5-FdUTP) is inserted into the telomerase instead of thymidine. This substitution disrupts the construction of the correct telomeres, and they cannot wrap the end sections of chromosomes. Cancer cells die after only a few days.
5-FdUTP has a related molecule –5-fluorouracil (5FU) – a toxic but effective drug for chemotherapy. Its cytotoxicity is traditionally associated with depletion of nucleotide pools. Now it has become clear that the full mechanism of 5FU is associated with its inclusion in RNA and DNA. Perhaps telomerase can also use it in the synthesis of telomeres. The action of 5FU became the justification for the use of its "sister" 5-FdUTP.
Normal cells in which telomerase works can also be affected by 5-FdUTP. Probably, such a sacrifice is acceptable. Another problem is that there are clear genetic indications for the treatment of 5FU that may apply equally to 5-FdUTP. The normal level of nucleotides is of great importance for the functioning of the immune system, as well as for neurotransmission at gabaergic synapses.
In the synapse system, metabolism occurs within the framework of the nucleosidome, a complex interaction of the extracellular nucleotide cascade system and intracellular nucleoside utilization. Mitochondria play the role of sensors of the nucleotide status and its translators along synapses. Recently, it has been proven that nucleotide flow through the mitochondria, specific to the serotonergic system, is the cause of diseases such as bipolar disorder.
Nucleotides and nucleosides have already proven their effectiveness in the treatment of various disorders associated with mitochondrial DNA. Their numerous analogues are also actively used in cancer chemotherapy, as well as for serious diseases such as AIDS.
Article by X. Zeng et al. Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner is published in the journal Cell Reports.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru .