File Name: telomere end replication problem and cell aging .zip
- Telomerase and telomeres in aging theory and chronographic aging theory (Review)
- Telomeres and telomerase
- Telomeres and telomerase
- Telomere and Its Role in Diseases
Linear chromosome ends are capped with nucleoprotein complexes called telomeres. Telomeres are essential for the integrity of chromosomes, and loss of the capping function caused by telomere shortening or deficiency of a capping protein leads to detrimental consequences, including the formation of abnormal chromosomes, permanent cell cycle arrest cellular senescence , and cell death apoptosis. Telomeres are thought to play a major role in preventing normal chromosome ends from being recognized and processed as DNA double-strand breaks DSBs.
As DNA polymerase alone cannot replicate the ends of chromosomes, telomerase aids in their replication and prevents chromosome degradation. Linear chromosomes have an end problem. To prevent this shortening, the ends of linear eukaryotic chromosomes have special structures called telomeres.
Telomerase and telomeres in aging theory and chronographic aging theory (Review)
Linear chromosome ends are capped with nucleoprotein complexes called telomeres. Telomeres are essential for the integrity of chromosomes, and loss of the capping function caused by telomere shortening or deficiency of a capping protein leads to detrimental consequences, including the formation of abnormal chromosomes, permanent cell cycle arrest cellular senescence , and cell death apoptosis.
Telomeres are thought to play a major role in preventing normal chromosome ends from being recognized and processed as DNA double-strand breaks DSBs. However, this telomerase-dependent mechanism is not the only solution to the end-replication problem in eukaryotic cells: a recombination-mediated mechanism has been found to participate in the maintenance of telomeres in several types of cells, including telomerase-defective yeast mutants, some immortalized tumor cells, and embryonic stem cells.
Thus, it is now becoming clear that the regulation of telomere replication impacts on development and disease in higher eukaryotes. In this chapter, we highlight recent topics in telomere biology, notably the regulation of telomere replication and the response to telomere dysfunction.
We focus on the molecular regulation of telomere replication during both the mitotic cell cycle and development, and discuss cellular responses to defects in telomere replication and their relationships with human diseases. The physiological importance of the telomere for chromosome maintenance has been known since the s, when the abnormal behavior of chromosomes lacking telomeres was described by two prominent cytogeneticists, Muller and Mclintock Muller, ; Mclintock, Meanwhile, the significance of the telomere as a replication machinery of linear chromosomes became clear after the mechanism of DNA replication at the biochemical level was explained, around However, the mechanism involved was still elusive at that time.
Various models to explain the solution of the end-replication problem in eukaryotic chromosomes were proposed in the s and s, but determination of the structure of the telomere and sequence of telomeric DNA sequence was necessary to determine which model was correct. Later, it was shown that similar sequences, with a signature of tandem repeats containing a cluster of G residues, were commonly found at the chromosomal termini in most eukaryotes.
The functional importance of the repeated sequence was proved in yeast by Szostak and Blackburn Usually, yeast plasmids replicate in a circular form; linearized plasmids cannot be maintained stably. However, when the terminal repeats of Tetrahymena were ligated to each end of a linear yeast plasmid, it was able to replicate in a linear form.
This result indicated that the terminal fragments served a conserved function to protect the ends of linear DNA. The conserved nature of telomeric repeats, both as double-stranded DNA and single-stranded G-overhangs, is critical for the recruitment of proteins involved in the formation and function of telomeres. Because of its specific sequence, telomeric DNA displays unusual properties. The G-quadruplex is a four-stranded helical structure composed of stacks of G-quartets that arise from the association of four guanines in a cyclic hydrogen-bonding arrangement.
The existence of G-quadruplexes at telomeres has been confirmed in vivo , and their functional roles have begun to be explained Smith et al. The G-overhang also contributes to formation of a higher-order structure: the t-loop.
The t-loop was first identified by electron microscopic analysis of in vivo -cross-linked human telomeric DNA, which was formed by the insertion of the G-overhang into the double-stranded region of telomeric DNA Griffith et al. Subsequently, t-loop structures have been found in telomeres in other organisms, suggesting that it is the conserved feature of telomere structure.
The solution of the end-replication problem by the telomere was confirmed by the discovery of telomerase by Greider and Blackburn Telomerase was identified in Tetrahymena as a specialized enzyme that adds the telomeric G-rich sequence to the end of linear DNA.
The addition of telomeric DNA by telomerase explained how the loss of terminal sequences caused by normal semi-conservative replication is counteracted. Telomerase is inactive in adult human cells, and telomere length gradually decreases during cellular senescence de Lange et al. By contrast, telomerase is activated after immortalization Counter et al.
Its catalytic subunit, identified by genetic screening in yeast Lendvay et al. Other telomerase-associated proteins have been described. They are thought to be involved in the biogenesis of telomerase or to regulate the recruitment of telomerase to chromosome ends. In both mammals and yeast, telomerase-positive cells maintain telomeres at a constant length. Newly formed short telomeres are elongated such that they reach the length that is characteristic of the particular cell type, while over-elongated telomeres shorten until they reach the normal length Negrini et al.
These observations indicate that telomerase activity is regulated at individual ends, and is regulated so as to counteract the loss of telomeric repeats due to the end-replication problem.
Recent studies have elucidated the regulatory mechanism that ensures length homeostasis at every telomeric end: the protein complex that binds at double-stranded telomeric DNA exerts an inhibitory effect on telomerase activity.
In budding yeast, the telomere dsDNA-binding protein Rap1 serves to limit telomere length: the number of repeats at an individual telomere was reduced when hybrid proteins containing Rap1 were targeted there by a heterologous DNA-binding domain Marcand et al. Through its C-terminal domain, Rap1 interacts with two proteins, Rif1 and Rif2. These two proteins act as telomerase inhibitors, andloss of either protein leads to telomere over-elongation Hardy et al.
Thus, a model has been proposed to explain the regulation of telomere length: longer telomeres carrying numerous Rap1 binding sites, leading to the increased binding of telomerase inhibitors, which repress telomerase-dependent telomere elongation.
Telomere length declines progressively with each replication cycle, causing the loss of telomere inhibitors at the ends of telomeres, allowing telomere repeat number to be restored by the action of telomerase. Consistent with this model, telomerase is not active at each telomere during every replication cycle, but is activated when the length of the repeat tract is reduced to a threshold level as a result of successive rounds of replication Teixeira et al.
Rap1 does not interact directly with Rif1 but, instead, interacts with Poz1, which serves as a negative regulator of telomere length Miyoshi et al.
The proteins directly bound to the very ends of chromosomes are not only essential for protecting telomeres but are also involved in recruiting telomerase to chromosomes. A budding yeast cdc13 mutant, originally isolated as a cell division cycle mutant, displays G 2 arrest after transfer to the restrictive temperature Hartwell et al. Cdc13 forms a complex with Stn1 and Ten1 in vivo Grandin et al.
As a result, CST has a strong affinity for single stranded telomeric DNA, and thus localizes to the very ends of chromosomes Taggart et al. Cell cycle arrest in the cdc13 mutant is due to loss of telomere protection: when CST function is disrupted, capping is dysfunctional and chromosome ends suffer the same fate as DSBs Garvik et al.
Cdc13 is phosphorylated at multiple sites by Cdk and Tel1 kinases Li et al. These modifications are thought to be important for recruitment of Est1 and telomerase to telomeres. Although the organization of DNA ends is well conserved, mammalian telomere ends are primarily protected by a Pot1-Tpp1 complex, part of the larger shelterin complex Wang et al.
Budding yeast CST and shelterin components do not have sequence similarity, suggesting that budding yeast may have a unique mode of telomere capping. However, recent studies have revealed that mammals and plants have Stn1 and Ten1 homologs, and that the two proteins form a complex with another protein called Ctc1 Miyake et al. One critical function of the telomere is assumed to be the prevention of normal chromosome ends being recognized as a damaged DNA ends.
This is mediated by the formation of a specialized nucleoprotein complex. Paradoxically, however, telomere length is reduced by mutations in DSB-detection machineries such as Tel1 and the MRX MreRadXrs2 complex, indicating that proteins involved in the recognition and repair of DNA damage are important for telomere homeostasis Greenwell et al. Therefore, these proteins are involved in telomere length control as components of the telomerase-dependent telomere elongation pathway.
As a mutation in replication protein C was also shown to lead to telomere elongation Adams et al. RPA localizes to telomeres during the S phase Schramke et al.
Yeast cells harboring an RPA mutation were shown to have shortened telomeres Ono et al. Telomeric DNA has the specialized structure described above, which may affect the progression of replication forks at the locus. Indeed, replication forks stall or pause at telomeres in yeast and human cells Ivessa et al. Such difficulties seem to be overcome, at least partially, by some of the telomere-binding proteins. For example, in fission yeast, Taz1 contributes to the efficient replication of telomeres by preventing fork stalling Miller et al.
RecQ-type DNA helicases have been shown to facilitate telomere replication, probably by relieving the secondary DNA structure at telomeres Sfeir et al. In budding yeast, the single-strand overhangs are present throughout the cell cycle, but are relatively short nucleotides for most of the cycle. The length of the overhangs increases transiently in the late S phase, during which telomere replication takes place Marcand et al.
Telomerase activity is indispensable for G-overhang formation during the S phase in yeast and mammals. Nucleolytic end processing activity also contributes to G-overhang formation Wellinger et al.
Their activity is regulated by the associated protein Sae2, a target of Cdk1 Huertas et al. However, at least in yeast, a redundant nucleolytic activity regulated by Sgs1 RecQ also controls end processing at telomeres Bonetti et al. Interestingly, the MRX complex only binds to leading-strand telomeres, and this binding is critical for the binding of the CST complex and telomerase to leading-strand telomeres Faure et al.
As described above, genetic analysis has shown that MRX and telomerase act in the same pathway. This suggests that telomere elongation probably occurs mainly at leading-strand telomeres, at least in yeast. Thus, temporal regulation may contribute to the difference between the two strands. In mammalian cells, differences in the behaviors of leading- and lagging-strand telomeres have been also reported, such as the preferential occurrence of telomere-telomere fusions between leading-strand telomeres upon shelterin inactivation Bailey et al.
Figure 2 presents a current model for telomere replication. In this model, telomere integrity is thought to be maintained by an elegant mechanism. The switch from a protected state to an accessible state allows telomerase recruitment. As discussed previously, this is achieved in both a cell cycle-dependent manner and a telomere length-regulated manner. Replication fork progression. In yeast, telomeres replicate during the late S phase Raghuraman et al.
Replication is initiated from a replication origin located in the subtelomeric region, and the replication fork moves towards the chromosome terminus. In mammalian cells, the timing of telomere replication seems not to be restricted to the late S phase Wright et al. End processing. After the replication fork reaches the terminus, C-strand-specific resection takes place to produce the G-overhang. Recruitment of telomere proteins. Single-stranded DNA-binding complexes are recruited to the extended G-overhang.
Recruitment of telomerase. Usually, recruitment of Tel1 to telomeres is inhibited by Rif1 and Rif2 Hirano et al. The conformation of short telomeres with reduced amounts of these two proteins changes to the accessible state, and Tel1 is thus recruited.
Tel1 phosphorylates Cdc13 and probably other proteins , thereby enabling it to interact with Est1 and permitting the telomerase to load to the ends of telomeres. It is not clear at present whether this regulatory mechanism is conserved among Tel1 orthologs in mammals and fission yeast. Telomere elongation and C-strand filling. G-overhangs are elongated by the action of telomerase.
The replicated telomere now returns to the protected state. Model for telomere replication in budding yeast. A: Fork movement towards the chromosome terminus. B: Telomerase-dependent telomere elongation.
In budding yeast, telomerase-defective mutants gradually lose their proliferation capacity because of telomere shortening.
Telomeres and telomerase
Although there are different architectures, telomeres in a broad sense, are a widespread genetic feature most commonly found in eukaryotes. In most, if not all, species possessing them, they protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double strand break. In the early s, Russian theorist Alexei Olovnikov first recognized that chromosomes could not completely replicate their ends. Building on this, and to accommodate Leonard Hayflick 's idea of limited somatic cell division, Olovnikov suggested that DNA sequences are lost every time a cell replicates until the loss reaches a critical level, at which point cell division ends. Gall , discovered the unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends.
Telomeres and telomerase
Journal of Cancer. International Journal of Biological Sciences. International Journal of Medical Sciences. Journal of Genomics.
This is an open access article distributed under the terms of Creative Commons Attribution License. Genetic information is stored in linear DNA molecules - chromosomes in eukaryotic cells 1. The different properties of chromosomes could be due to the presence of special nucleotide sequences at the chromosomal ends, which are called telomeres 4. Telomeres consist of repeating nucleotide sequences and a set of special proteins that interact with DNA to form a nucleoprotein complex 5.
Recently, short telomeres have become a widely accepted cellular hallmark of aging. Telomere lengths in a single cell are heterogeneous and it is believed that the shortest telomere in a cell drives the induction of senescence. Hence, measuring the shortest telomere lengths not just average can provide more information about aging, cancer progression and telomere related diseases. Chronic exposure to DNA damaging agents, oxidative stress, inflammation, smoking, alcohol, exposure to acute and chronic stress promote telomere shortening and earlier onset of cell aging. Healthy life style including Mediterranean diet, moderate exercise, managing stress breathing, meditation, yoga , spending time with loved ones and lots of laughter will help us to keep our telomeres long and safe.
Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Its scope is unique.
Telomere and Its Role in Diseases
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Immortal eukaryotic cells, including transformed human cells, apparently use telomerase, an enzyme that elongates telomeres, to overcome incomplete end-.
Mechanism of Aging and Telomeres
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