Question

Briefly what is the evidence that telomerase activity or lack thereof is involved in tumorigenesis?

Answer 1

Chromosomes ends are protected by telomeres which are repetitive (TTAGGG) DNA–protein complexes at the ends of chromosomes. They are important for the survival of cancer cells. they mask telomeric DNA present at the end of the chromosome by preventing them to undergo recombination and fusion. They cap the ends so that they can go unnoticed by the DNA surveillance pathways.  They are maintained by an enzyme called telomerase in the vast majority of tumours.

When Telomere shortening is happening as a result of cell division due to the “end replication problem” in which the lagging strand DNA synthesis cannot be completed all the way to the very end, This leads to increased cell divisions with shortened telomeres which increases DNA damage responses that trigger cellular senescence(loss of a cell's power of division and growth). The p-53 and p16-RB pathways are often activated leading to irreversible growth arrest in cells undergoing replicative senescence. The cells that gain oncogenic changes or p53 loss can bypass senescence and continue to divide until a critically shortened telomeres initiate a crisis. During this period an only a rare human cell can bypass this and become mortal. This is usually accomplished by upregulation or reactivation of telomerase. Also,  telomerase negative immortalization pathway, termed ALT (alternative lengthening of telomeres), is involved in DNA recombination to maintain telomeres.

This can be explained in the following figure.

Normal dividing cell Multiple replications, progressive telomere shortening Abrogation of p53 and/or p16/Rb tumor suppressor pathways Extended lifespan Threshold short telomere length Cellular senescence M1 phase DNA damage activation Loss of cell cycle checkpoint control Crisis - M2 phase Uncapped telomeres Chromosome end-to-end fusions .... Cell death Incipient immortal cell High genomic instability Dysfunctional telomeres Extensive cell death due to mitotic catastrophe hTERT or ALT activation 2 Immortal cancer cell

Source:

Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies

Mohammad A. Jafri, Shakeel A. Ansari, Mohammed H. Alqahtani, and Jerry W. Shay