By Edgar Wex
Since the discovery of the telomere and its role in DNA replication, the idea of an extended lifespan and even immortality have been more seriously reconsidered from the scientific perspective. Throughout human history philosophers dreamt of an immortality elixir; manipulating the telomerase enzyme may be a step in the right direction.
To understand how telomeres are important, we must first understand how they work and why they exist. DNA is double stranded; and each of these strands are complementary to each other and run in opposite directions. Due to the molecular structure, there is a 5’ (5 prime) end, where the last carbon of deoxyribose binds to the next phosphate, and a 3’ (3 prime) end, where the 3rd carbon does the same but on the other side. Replication works by extending the -OH group on the 3’ end of the DNA strand - this means that, as one strand runs 5’ to 3’, and the other strand runs 3’ to 5’, one strand can be synthesised continuously while the other must be done backwards in sections. On the leading strand; when DNA polymerase attaches to it, it can quickly add deoxyribonucleotides and extend it, until it falls off at the end. In reality is it much more complex, with multiple polymerases working on the same long strand starting at multiple origins, with multiple forks and running into errors and falling off early, however the general principle is the same.
The other strand (lagging strand) is more complicated as it requires the use of multiple small DNA primers and replication in small steps. This is because the replication fork set up must move in one direction, so DNA is synthesised in a stable way. The diagram below shows the oversimplified mechanism.
The polymerase on the lagging strand can only move left, which is the 5’ to 3’ direction. However, DNA must be replicated moving right. Thus, as the replication fork moves right and new single stranded DNA is exposed, small RNA primers are attached, which are extended by the polymerase until they reach the previous primer. Then the next primer is attached, and the polymerase synthesises another small amount of DNA until it reaches the primer from before. The RNA left in the lagging strand DNA is then fixed as part of the Okazaki fragment repair process, and then replication is in principle complete.
The problem arises at the end of the chromosome - while the leading strand just keeps going until there is no DNA left, the lagging strand will have a small section left unreplicated. This is because during okazaki fragment repair, the next primer towards the end of the chromosome is used to bridge the gap between DNA sections when the RNA is removed. However, at the end, at the last fragment, there is no primer further down to extend from. Thus, every time the chromosome is replicated, at least 1 primer worth of length is lost from the DNA strand, which in practicality is around 100 to 200 base pairs. For the next cycle of DNA replication, the already shorter template is used; the leading strand replicates the whole thing, however because it is initially shorter there is still overall DNA lost. And on the lagging strand, still more is lost due to the same issue. This repeats in each cycle of replication until the cell would reach a state of crisis and would kill itself.
This is avoided through the use of the telomeres. These are sections of DNA composed of the TTAGGG sequence repeated a few times, with a 3’ -OH ending. These protect the chromosome ends from degradation by looping back on themselves, act as origins for lagging strand synthesis to start from, and are lost instead of coding DNA, protecting the cell. The telomerase enzymes maintain the length of these by extending the ends of the chromosomes, however over many, many replication cycles, the telomeres are still shortened.
This diagram shows how telomerase extends the telomeres. It contains a fixed section of RNA; 1.5 loops of the repeated sequence, with the U base instead of a T. It continuously rebinds to add 3 bases at a time to the telomere. Telomerase activity is controlled by telomere binding proteins; these attach to the telomeres and negatively regulate the activity of telomerase. Thus, as the telomere gets longer, more of these attach, the telomerase is inhibited more and works less, until at some point it stops working, leaving a good length of extended telomere.
Thus, telomerase, with its ability to extend telomeres, would be desired in every cell. However, only stem cells have a substantial amount of it, meaning that normal cells are given a limited lifetime and number of divisions. This is because with too much replication, there is a high risk of cancer, which is characterised through the immortality of cells that uncontrollably replicate (over 85% of cancers overexpress telomerase). Thus, this leaves 2 opportunities for development. Telomerase could be somehow reactivated in a controlled way to allow all the replicating cells in the body to continue doing so indefinitely, and telomerase could be inhibited as part of anticancer treatments.
References
Images
No changes were made, https://flic.kr/p/SEG81X, License: Creative Commons Legal Code
Diagrams - Drawn
What did you learn?
How do telomeres give cells a limited lifetime?
During replication, the lagging strand of DNA cannot be fully replicated; this is because DNA must be replicated in one direction, while the polymerase enzyme runs in the other direction. Thus it has to replicate small sections and keep jumping backwards. However, at the end of a chromosome, there is no primer to replicate across the last okazaki fragment, which leads to the loss of DNA each time it is replicated. Telomeres are sections of a repeated sequence of DNA added to the end of the chromosome so that they are lost instead of coding DNA.
How can we use telomerase medically?
Telomerase can be inhibited in cancer cells, which will slow their growth by removing their immortality. It can also be used in a science fiction way to try and give normal body cells immortality, thereby extending our overall lifespan, however it is unknown how to do this and avoid causing cancer.