By Marcia-Ruth Ndege ‘21
The telomerase enzyme catalytic cycle limits the telomerase enzymes’ ability to synthesize specific DNA segments of six nucleotides called repeats. These repeats, known as telomeres, are protective caps that prevent the destabilization of the genome by lengthening the ends of chromosomes. However, these protective caps shorten every time a cell divides. A cell’s telomere length, therefore, determines when a cell will stop growing and begin aging. Lengthening the ends of telomeres by synthesizing short DNA repeats on chromosome ends, telomerase extends the lifespan of the cell. Research done by Professor Julian Chen in the School of Molecular Sciences at Arizona State University shows that targeting a step in the telomerase catalytic cycle may allow telomerase to synthesize these repeats without restraint.
Professor Chen and her team proposed that increasing the rate of telomere production to surpass the rate of telomere length reduction would rejuvenate adult stem cells. Increasing this rate of production requires bypassing an intrinsic pause signal that exists within telomerase: the nucleotide sequence (GGTTAG) in the RNA template tells the enzyme to stop synthesizing DNA. Chen found that telomerase achieved its highest rate of production in the presence of high concentrations (between 20 and 50 μM) of deoxyguanosine triphosphate (dGTP), which is the precursor of the G nucleotide and therefore required for DNA synthesis. Increasing dGTP concentrations increased G nucleotide concentrations; as a result of increased substrate concentrations, telomerase was able to overcome the pause signal.
Although these findings are promising, there is another factor to consider. Cancer is defined as uncontrolled cell division that produces masses of cells – tumors – within the body. If cancer cells were to be exposed to treatments that increase telomerase function, their life spans would increase, allowing them to cause further destruction. In fact, such treatment has the potential to put at risk for cancer people who are not already at risk. Therefore, researchers are doing their best to synthesize drugs that increase telomerase activity exclusively within stem cells and not within somatic cells.
- Y. Chen, et. al., A single nucleotide incorporation step limits human telomerase repeat addition activity. EMBO (2018). doi: 10.15252/emboj.201797953.
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