Abstract
Telomeres facilitate the protection of natural ends of chromosomes from constitutive exposure to the DNA damage response (DDR). This is most likely achieved by a lariat structure that hides the linear telomeric DNA through protein-protein and protein-DNA interactions. The telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in unmasked telomeres. Then, the subsequent activation of the DDR will define the fate of cells according to the functionality of cell cycle checkpoints. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptotic pathways, but they can also promote tumour initiation. Studies in telomere dynamics and karyotype analysis underpin telomere crisis as a key event driving genomic instability. Significant attainment of telomerase or alternative lengthening of telomeres (ALT)-pathway to maintain telomere length may be permissive and required for clonal evolution of genomically-unstable cells during progression to malignancy. We summarise current knowledge of the role of telomeres in the maintenance of chromosomal stability and carcinogenesis.
Highlights
Telomeres facilitate the protection of natural ends of chromosomes from constitutive exposure to the DNA damage response (DDR)
In agreement with this observation, super-resolution microscopy analysis has shown that human telomeres, in vivo, form hyper-compact globular chromatin structures through specific protein-protein and protein-DNA interactions between shelterin subunits and telomeric DNA that is essential for end protection
Most importantly, p53 mutations in late generation telomerase null mice produced a shift in the tumour spectrum towards epithelial cancers, the tumour type most frequent in aged humans, reinforcing a connection between telomeres and carcinomas [149]. These findings demonstrate that telomere uncapping, either through loss of the G-rich overhang itself or by critically shortening the (TTAGGG)n tract of DNA, can trigger, in the setting of p53 deficiency, the genome instability that promotes the development of epithelial cancers
Summary
The first evidence of telomeres, specialised nucleoprotein structures that protect the end of chromosomes, was observed in flies and maize [1,2]. One of the main functions of shelterins is to remodel the linear telomeric DNA to form a lariat structure that differentiates the chromosome end from a double-strand break (DSB) This arrangement is achieved through the invasion and pairing of the G-rich 3′ overhang into the. This arrangement is achieved through the invasion and pairing of the G-rich 3 overhang into the preceding C-strand of the ds-telomeric tract while the telomeric G-strand is displaced. These data underscore a more complex picture for telomere structure organisation and end protection
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