Therapy Analysis - Telomerase as a potential therapeutic target
Telomeres
...How do our cells have any DNA left? The answer is telomeres. Human telomeres are repeated TTAGGG nucleotide sequences on the ends of chromosomes ending in G-rich single-stranded 3' overhangs, forming a lariat structure called a 't-loop'...Telomerase was discovered by Carol Greider and Elizabeth Blackburn in 1984 in the ciliate Tetrahymena. Blackburn noticed that the DNA on the ends of chromosomes was actively growing and shrinking, and hypothesized that a form of reverse transcriptase must be at work. When DNA replicates during cell division, an RNA primer is required to allow the cellular machinery to copy the DNA strand. Since the primer will rarely attach to the very end of the replicating strand, the new copy will be missing a stretch of DNA - this is known as the ‘end replication problem’. This process will be repeated each time the cell divides, with the copied DNA strand losing more of the end section every cycle.
This leads to the question: How do our cells have any DNA left? The answer is telomeres. Human telomeres are repeated TTAGGG nucleotide sequences on the ends of chromosomes ending in G-rich single-stranded 3’ overhangs, forming a lariat structure called a ‘t-loop’ They are analogous to the plastic tips on shoelaces, preventing both the loss of essential sequences during replication cycles and chromosome ends from fraying and ‘sticking’ to one another. In germline cells, telomerase is the enzyme responsible for the addition of these repeat sequences to the ends of chromosomes, thus making these cells effectively immortal. Normal somatic cells also contain basal telomerase activity levels when they have first developed, but do not endogenously express telomerase. The level of telomerase in their progeny is therefore decreased markedly with every division, and is insufficient for telomere upkeep, so their telomeres grow shorter and the cells age. Cells can normally divide 50 to 70 times, with their telomeres getting progressively shorter, until the cells senesce or die.
Human telomerase is an RNA-protein complex, consisting of a telomerase reverse transcriptase catalytic subunit (hTERT), and an RNA component (hTR) acting as a template for adding telomeric TTAGGG repeats to the end of the chromosome.
As a mutated cell progresses to becoming cancerous, collecting more and more mutations on the road to malignancy, it divides more often. If its telomeres get too short the cell may halt division, enter senescence, and eventually die. The cell can escape such a fate if it coincidentally achieves telomerase activation in the course of random mutation, which will prevent further telomere shortening. A rare cell which gains telomerase activation and maintains telomeres therefore becomes effectively immortal, much like a stem cell, and this is hypothesised as a critical step in cancer progression. Studies have found high levels of telomerase activation in many types of cancer, including approximately 90% of breast cancers. Thus, telomerase could be an ideal diagnostic or prognostic marker for cancer progression, or even an alternative therapeutic target.
