What is the Clinical Significance of Telomeres?

By Chandan Sekhon - Medicine Student @ Peterhouse, Cambridge

Telomeres are vital structures found at the end of chromosomes, composed of repeat DNA sequences. Whilst these structures are not completely understood, we know they have a key role in DNA replication.

DNA is composed of two antiparallel strands with one strand running from the 3’ to 5’ direction (the leading strand), and the other strand running from the 5’ end to the 3’ end (the lagging strand). Whilst the leading strand is readily replicated (as the DNA polymerase enzyme responsible for DNA replication works in the 3’ to 5’ direction), the lagging strand runs in the opposite direction and so must be replicated in short fragments instead which are then joined together after replication is complete. In order to initiate replication, RNA primers must be added to the segments to be replicated at the origin of replication. As the leading strand is replicated continuously, only one primer is needed for this strand. However, the lagging strand is replicated discontinuously, and so needs multiple primers. This mechanism of replicating the lagging strand means that the ends of the chromosome are not replicated. If this is not corrected, then it is possible that the subsequent generation which inherits these chromosomes will have lost some genetic information (as the region covered by the RNA primer would not be replicated). This can have extremely dangerous consequences for the affected individual, and can result in a variety of genetic conditions, or lead to premature death.

In order to overcome this issue, eukaryotes have developed telomeres. These are protective agents preventing the loss of genetic information which act as ‘caps’ to seal the ends of DNA strands, thus preserving the genetic information contained within them. Prokaryotes do not need telomeres, however, as they have circular DNA so do not need mechanisms to prevent the ends of DNA from fraying. In humans, the base sequence TTAGGG is repeated approximately 1000 times in telomeres and is added to DNA by the enzyme telomerase. Interestingly, every time a cell divides, the length of telomeres shortens, as they don’t have enough telomerase. Once telomeres reach a critical length, cells read this as getting old and stop dividing (this is known as the Hayflick limit). If telomerase is re-introduced, the cell can continue dividing. This may cause issues in cancerous tumours, where some tumours have elevated telomerase levels (which could contribute to their persistence).

Dyskeratosis congenita (DC) is a rare congenital disorder which arises from mutations in genes which code for the synthesis of proteins which maintain telomeres. This condition can increase the risk of developing cancer in later life. This is thought to be because telomeres are abnormally maintained. It has been noted that patients with DC have highly shortened telomeres which contributes to the effects of the condition, including dystrophy of nails and hyperpigmentation of skin. Roughly 10% of sufferers die due to cancer. Consequently, research around telomeres may provide insights into cancer growth and survival, and a lot of research centres around testing whether possible anti-cancer drugs could be telomerase inhibitors.

Further reading:

  1. Article titled ‘Telomeres, lifestyle, cancer, and aging’ which gives an introduction to telomeres and how these three modalities affect them: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370421/

  2. Interesting article about the relationship between telomeres and ageing: https://www.healthline.com/health/telomeres#telomere-lengthening

  3. Article about Dyskeratosis congenita (DC) which outlines the disease in detail, including the causes, symptoms and treatments for it: https://rarediseases.org/rare-diseases/dyskeratosis-congenita/#:~:text=Dyskeratosis%20congenita%20is%20a%20rare,tissue%2C%20and%20congenita%20means%20inborn