Abstract
Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.
Highlights
Telomeres are conserved tandem repeats at chromosomal ends that differ in length in diverse species [1,2,3,4,5]
The telomeres, organized within tightly packed histone octamer composed nucleosomes (Figure 2), are stabilized through specific protein–protein and protein–DNA interactions between shelterin subunits with histone 3 trimethylated at lysine 9 (H3K9me3) and histone 4 trimethylated at lysine 20 (H4K20me3)
Telomerase consists of a catalytic subunit, telomerase reverse transcriptase (TERT), and an RNA component (TERC), which acts as a template for the extension of telomeric nucleotide repeats [6,98,99]
Summary
Telomeres are conserved tandem repeats at chromosomal ends that differ in length in diverse species [1,2,3,4,5]. Single-stranded 50–300 nucleotide guanine rich telomeric G-tail folds back into the duplex DNA to form a t-loop (Figure 1B) that resembles a large “lariat-like” structure [1,17,18]. The G-tail can fold into a four-stranded helical structure known as the G-quadruplex (Figure 1C) that involves stacking of G-quartets and intra-molecular folding by overcoming kinetic barriers, with each quartet formed by the association of four guanines into a cyclic Hoogsten hydrogen-bonding arrangement [19,20]. Cancers 2020, 12, 558 quartets and intra-molecular folding by overcoming kinetic barriers, with each quartet formed by the association of four guanines into a cyclic Hoogsten hydrogen-bonding arrangement [19,20]. Adapted from [23,24]
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