Telomere maintenance in cancer cells Schematic images of A the Biology Diagrams Telomeres are distinctive structures that protect the ends of linear chromosomes and ensure genome stability. They are composed of long tracks of repetitive and G-rich DNA that is bound by shelterin, a dedicated six-subunit protein complex. In somatic cells, shelterin protects telomeres from the DNA damage response and regulates telomere length. Telomere repeats are replenished by telomerase This event then stimulates DDR pathways, leading to increased expression levels of the cell cycle inhibitors p16 and p21, which in turn restrain proliferation [3,4]. Despite being shortened, these telomeres still maintain an adequate number of telomere-binding proteins to prevent fusion and block DNA repair [5-8]. This process fuels a The telomere-shelterin complexes that cap all eukaryotic chromosomes ensure that healthy cells can progress through the cell cycle by preventing the cellular DNA damage response from identifying chromosome ends as double-stranded breaks (DSBs). [4] [5] Without a protective cap, chromosome ends would appear identical to intrachromosomal DSBs.These DSBs activate a DNA damage response pathway
The direct regulation of TR transcription by E2F1-Dp suggests a model in which telomere addition is synchronized with cell-cycle progression. This illustrates a robust coupling between the TR life cycle and host cell-cycle machinery, ensuring effective telomere maintenance and genomic stability throughout multiple rounds of cell divisions . Summary of mechanisms by which the DNA damage response is repressed at telomeres or harnessed to facilitate telomerase-mediated telomere maintenance. (A) Shelterin protects telomeres from inappropriately activating a DNA damage response in phases of the cell cycle when the telomere can fold into a t-loop. TRF2 promotes t-loop formation, which Telomere maintenance requires the telomerase and a network of telomere-associated proteins, (TIF), telomere end-end fusion, and ultimately cell cycle arrest, senescence, and genome instability [13, 14]. In human, telomere dysfunction has been implicated in bone marrow failure syndromes, leukemia, and cancer development [9, 10, 15
Transcriptional coupling of telomeric retrotransposons with the cell cycle Biology Diagrams
The basic N-terminal domain of TRF2 limits recombination endonuclease action at human telomeres. Cell Cycle 13, to DNA replication and repair and telomere maintenance. Mol. Biol. Cell 23, The role of telomere attrition and damage in inducing permanent cell cycle arrest was further demonstrated using human fibroblasts overexpressing a mutant form of TRF2 ensures proper telomere maintenance in normal cells. At the same time, each of these features is vulnerable to mutations and dysregulation, leading to familial and sporadic
However, repair at telomeres was only observed in proliferating cells, such as BJ fibroblasts and HeLa cells. Interestingly, HeLa cells, which are faster dividing cells, display a faster repair kinetics compared to slower dividing fibroblasts, suggesting that proliferation rate is an important determinant of telomeric DSB repair (Mao et al., 2016).
