Telomere length monitoring program

Telomeres represent both genomic sacrifice zones which prevent the loss of genomic information at the end of chromosomes and high order structures masking chromosome end from being detected as DNA breakage site by the DNA damage response machinery. Also, telomeres regulate gene expression, transcriptionally silencing genes both close to them and/or at long distances.

Telomere functions depend on a minimal length of DNA repeats. Unfortunately, during progressive cell divisions they critically shorten. This phenomenon generates dysfunctional structures able to elicit DNA damage responses. Consequently, cellular senescence is triggered, and cells undergo an essentially irreversible growth arrest.

Telomere shortening is a natural phenomenon occurring with aging. Inflammation and oxidative stress, two major pathways of carcinogenesis, accelerate this process

The progressive telomere shortening is particularly dangerous when combined with oncogenic changes such as loss of the function of p53, a protein that stops cell proliferation and induces senescence, or of other cell-cycle regulators. In fact, these changes can bypass the period of replicative senescence imposed by telomere shortening, further promoting telomere attrition. If mechanisms to maintain very short telomeres develop, cancer can arise. In 85-95% of cancers, such mechanisms involve telomerase activation by expression of the hTERT gene.

Maintaining shortened telomeres allows the cell to express specific genes required for cancer progression that would be otherwise silenced. Also, it can promote chromosomal instability, significantly contributing to genomic rearrangements associated with tumorigenesis.

In the majority of cells high genomic instability leads to cell death. However, in rare cells the activation of telomerase enables the generation of transformed cells with a heavily rearranged, stabilized, genome enriched with potentially tumorigenic mutations. It is sufficient telomere loss at individual chromosome ends to wreak havoc on the genome.

Longer telomeres can confer a longevity advantage too. They may be permissive for increased replicative potential of cells acquiring mutations that would otherwise undergo cell death, increasing the opportunities to develop genomic instability, and promoting cancer development.