Two mutations allow cancer cells to lengthen telomeres without telomerase
Most actively dividing malignant cells become "immortal" due to the activation of the telomerase gene, which does not work in most normal cells, an enzyme that restores telomeres after each division. Sometimes tumor cells use another mechanism – alternative telomere elongation by homologous recombination – the exchange of DNA sections between paired chromosomes.
But, as it turned out, there is at least one other alternative way to lengthen telomeres in cancer cells. Researchers at Johns Hopkins University, working under the guidance of Associate Professor Alan K. Meeker, identified two genes whose defects are associated with this phenomenon in 100% of cases.
The first prerequisites for the discovery were obtained by processing the results of mapping the genome of neuroendocrine tumors of the pancreas. The most characteristic genetic disorders of these tumors were mutations of the ATRX and DAXX genes. The protein products of these genes interact with certain DNA fragments, including telomeres, and change the principle of "reading" the sequences encoded in them.
This observation prompted scientists to study in more detail the relationship of these genes with the preservation of telomere length. The study of 41 tissue samples of patients with neuroendocrine tumors of the pancreas, conducted by fluorescent staining of large telomerase DNA conglomerates, revealed signs of alternative telomere elongation in 25 of them.
Pink dots – alternatively lengthening telomeres
in the cells of the neuroendocrine tumor of the pancreas.
In normal cells, there are 100 times fewer telomerase sequences.
Mutations disrupting the ATRX or DAXX genes were found in the cells of 19 of these 25 samples. In the cells of the six remaining samples, the expression of these genes was not recorded at all – obviously, both genes in them were damaged and did not function.
Thus, the researchers found a one-hundred-percent correlation between the anomalies of the ATRX and DAXX genes and alternative telomere elongation.
Gene expression analysis of aggressive glioblastoma brain tumor samples also demonstrated the existence of a relationship between ATRX gene mutations and alternative telomere elongation.
To date, researchers have not yet known the mechanisms by which the ATRX and DAXX genes affect telomere elongation. They suggest that mutations of these genes change the nature of folding of the DNA chains forming telomeres, increasing their instability.
The authors also note that patients with mutations of identified genes are characterized by a higher survival rate. Therefore, in addition to the development of new therapies, the data obtained can form the basis of new methods for predicting the course of malignant diseases.
Article by Christopher M. Heaphy et al. Altered Telomeres in Tumors with ATRX and DAXX Mutations was published on-line on June 30 in the journal Science Express.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Medical Xpress materials:
Two genes linked to why telomeres stretch in cancer cells.
01.07.2011