Abstract
Telomeres are areas of heterochromatin composed of TTAGGG repeats located at the ends of linear chromosomes. They play a critical role in keeping genome stable and preventing premature aging diseases and the development of cancer. Characterizing mechanisms of telomere maintenance and understanding how their deregulation contributes to human diseases are therefore important for developing novel therapies. A key mechanism driving telomere maintenance and replicative immortality in cancer cells is telomere elongation by telomerase, and many emerging potential telomere-based therapies have focused on targeting telomerase components. By contrast, recent studies on telomere maintenance mechanism suggest that disrupting telomere stability by interfering with alternative mechanisms of telomere synthesis or protection may also yield new strategies for the treatment of cancer. This review will focus on emerging regulators of telomere synthesis or maintenance, such as G4 telomeric DNA, the CST complex, the t-loop, and shelterins, and discuss their potential as targets for anti-cancer chemotherapeutic intervention in the future.
Highlights
Telomeres are areas of heterochromatin composed of TTAGGG repeats located at the ends of linear chromosomes
Telomeres have three functions: first, telomeres protect the ends of chromosomes and facilitate their replication by telomerase; second, telomeres prevent recognition of chromosome ends as breaks and suppress DNA damage response (DDR) [5,6]; and last, recent work suggests that telomeres are emerging as potential sensors of genotoxic stress [7]
It is important to understand the mechanisms of telomere maintenance and how telomere instability, which contributes to human diseases and genomic instability, may arise
Summary
Telomeres are areas of heterochromatin composed of TTAGGG repeats located at the ends of linear chromosomes. If the p53 or Rb checkpoint pathway is deficient, cells continue to divide and the short unstable telomeres induce chromosome end-to-end fusions, leading to genome instability that drives oncogenesis. In addition to telomere shortening, telomere instability can occur when inappropriate secondary structures of telomere DNA, such as G-quadruplexes, form Formation of these structures can interfere with telomere DNA synthesis by stalling replication forks at the telomeric region [26,27], leading to telomere fragility and possibly rapid loss of telomeres or elevated recombination [28,29,30,31,32,33]. In addition to telomere shortening, telomere instability can result from telomere deprotection induced by deficiency in telomere binding proteins due to loss of DDR suppression and increased genomic rearrangements [34,35,36] (Figure 1B). Repaired [37], accumulation of telomere damage can be a source of genomic instability in cells
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