Why telomere shortening slowing down cancer?

Question

I am reading Alternative Lengthening of Telomeres in Mammalian Cells, about how telomeres linked to human cancers.

Due to the end-replication problem,5,6 the ends of linear chromosomes shorten with each round of DNA replication.7 In human somatic cells, the progressive telomere shortening that occurs with continued proliferation eventually results in the triggering of a replicative checkpoint. Telomere shortening and the structural changes that it presumably causes, leads to a DNA-damage checkpoint response at the telomere and induction of a permanent p53- and Rb-dependent growth arrest (i.e., replicative senescence).8-10 Because this limits the proliferative capacity of somatic cells, including those that have accumulated oncogenic mutations, telomere shortening and replicative senescence are a potent tumor suppressor mechanism.

The paragraph states a shorter telomere is a potential suppressor to cancers. Why is that? Why exactly a somatic cell proliferate slower with a shorter telomere DNA sequence?

Conversely, why a longer minority leads to human cancers?

Answer 1

Think about the 24 different linear chromosomes in a diploid human XY cell. In the absence of active telomerase enzyme to repair the chromosome ends following one round of cell division, then every time that cell divides each end of each chromosome will get a little bit shorter.

If the cell keeps dividing indefinitely, like a tumor cell, the chromosomes are effectively shrinking. Eventually this chromosome shortening will result in deleting actual genes (at first, 24 chromosomes x 2 chromosome ends = 48 genes). Not all of those genes are essential for cell viability; and the distance, or length, of DNA between the telomere and the first gene on that end will be variable. But as soon as the chromosome shortening removes part of an essential gene, then that cell will quickly die.

It would be like erasing the words at both ends of a sentence, one letter at a time. In the beginning, someone else would still be able to make sense out of your sentence, but eventually they would not be able to fully understand what information you were trying to convey.

Most of the terminally differentiated cells in an adult human are no longer actively dividing, so it is not a problem, they don’t need active telomerase. However, cancer is a condition of unregulated cell division, and so all cancer cells have to have some mechanism of repairing the ends of their chromosomes. Reactivation of TERT (Telomerase Reverse Transcriptase, the protein component of the telomerase enzyme) gene expression is extremely common in cancer cells.