The telomere represents a nucleoprotein complex found at the termini of eukaryotic chromosomes, and its repetitive DNA sequence known as telomeric DNA is maintained in a loop structure. Several different mechanisms related to DNA replication, repair and remodeling are responsible for the loss of telomeric DNA.
Some of the aforementioned processes take place at every chromosome end during every cell cycle, whereas others arise infrequently as a result of replicative errors or DNA damage. The sporadic nature of telomere loss due to the latter events complicates the study of telomere shortening and mostly results with ignoring the problem.
Loss of telomere repeats with replication
Studies in yeast have shown that telomeres are replicated from internal replication origins with replication forks moving toward the ends of chromosomes. The inevitable loss of nucleotides resulting from lagging-strand DNA synthesis of linear chromosomes was recognized as the end-replication issue in the early 1970s.
Processing of the blunt ends that are produced by leading-strand DNA synthesis is necessary to produce a single-strand 3’ overhang with subsequent “T-loop” formation. Although such exonuclease processing has to be tightly controlled, it results in variable degree of telomere trimming.
Recombination and oxidative damage
Telomeres can also get shorter as a consequence of oxidative damage; telomeric DNA that is rich in guanine shows a high degree of vulnerability to oxidative stress in comparison to genomic DNA. In such instances, nucleotide excision pathways are used to repair the affected nucleotides.
Conversely, oxidative lesions such as single-strand breaks may result in loss of telomeric DNA. It must be noted that the influence of oxidative lesions to telomere trimming could vary over time as a function of the amount of oxygen radicals produced, or the redox balance of the cells.
Despite the repetitive nature of telomeric DNA, telomeres show remarkable resistance to recombination events. Still, intrachromatid recombination has been described as a way to control the size of telomeres in yeast, and similar mechanisms that trim telomeres have been demonstrated in human cells as well.
Syndromes of telomere shortening
Prototypic syndromes linked to short telomeres are premature aging syndromes with degenerative and vascular components. In addition, there is a broad spectrum of diverse clinical syndromes linked to telomere shortening which include commonly observed age-related disorders that were previously thought to be idiopathic, such as idiopathic pulmonary fibrosis.
A role of telomere shortening in carcinogenesis is twofold; it inhibits tumor formation, but it can also lead to cancer initiation due to the promotion of genome instability. Thus it is of no wonder that short telomeres are commonly observed as an early marker in cancer formation.