Stressed ends: telomere attrition in chronic diseases

Telomeres are DNA-protein structures that cap chromosomal ends and protect them from degradation.In vertebrates, these sequences are composed of long stretches of TTAGGG repeats that can extend for up to 15 kilobases (kb) in humans and 100 kb in rodents.The telomeric DNA is composed of a long double-stranded tract that ends in a short, single-stranded overhang.Telomeric DNA is bound by shelterin, a large multisubunit protein complex that prevents the chromosome ends from being recognized as a DNA break, and inhibits inappropriate recombination.Inhibition or deletion of specific shelterin components results in a local DNA damage response at chromosome ends, leading to robust activation of DNA damage pathways and cell death.Due to the inability of DNA polymerases to fully replicate chromosome ends at the lagging strand, at every cell division there is a loss of up to 200 base pairs of telomeric DNA. 1 It is suggested that critically short telomeres carry insufficient shelterin components to avoid ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and 'rad3-related' (ATR) signaling cascades. 2Accordingly, cells with short telomeres present classical DNA damageresponses, such as formation of telomere(definition) induced foci (TIFs), stabilization of p53, and activation of p21. 2 The telomerase ribonucleoprotein, which is able to synthesize telomeres from an RNA template, provides a compensatory mechanism to continuous telomere shortening. 3In humans however, telomerase is only active in stem and progenitor cells, and is not able to maintain telomere length throughout lifespan. 4In this regard, telomere shortening can be seen as a molecular clock for cellular aging.