scholarly journals Telomeres and Cancer

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1405
Author(s):  
Hueng-Chuen Fan ◽  
Fung-Wei Chang ◽  
Jeng-Dau Tsai ◽  
Kao-Min Lin ◽  
Chuan-Mu Chen ◽  
...  
Keyword(s):  
Telomere Length ◽  
Molecular Mechanisms ◽  
Telomere Maintenance ◽  
Cancer Development ◽  
Telomere Elongation ◽  
Metabolism Pathway ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Genome Protection

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.

scholarly journals The Role of Rif1 in telomere length regulation is separable from its role in origin firing

2020 ◽  
Author(s):  
Calla B. Shubin ◽  
Carol W. Greider
Keyword(s):  
Telomere Length ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Origin Firing ◽  
Replication Complex ◽  
Telomere Elongation ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Telomere Lengthening

AbstractTo examine the established link between DNA replication and telomere length, we tested whether firing of telomeric origins would cause telomere lengthening. We found that RIF1 mutants that block Protein Phosphatase 1 (PP1) binding activated telomeric origins but did not elongate telomeres. In a second approach, we found overexpression of ΔN-Dbf4 and Cdc7 increased DDK activity and activated telomeric origins, yet telomere length was unchanged. We tested a third mechanism to activate origins using the sld3-A mcm5-bob1 mutant that deregulates the pre-replication complex, and again saw no change in telomere length. Finally, we tested whether mutations in RIF1 that cause telomere elongation would affect origin firing. We found that neither rif1-Δ1322 nor rif1HOOK affected firing of telomeric origins. We conclude that telomeric origin firing does not cause telomere elongation, and the role of Rif1 in regulating origin firing is separable from its role in regulating telomere length.

scholarly journals The role of Rif1 in telomere length regulation is separable from its role in origin firing

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Calla B Shubin ◽  
Carol W Greider
Keyword(s):  
Telomere Length ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Origin Firing ◽  
Replication Complex ◽  
Telomere Elongation ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Telomere Lengthening

To examine the established link between DNA replication and telomere length, we tested whether firing of telomeric origins would cause telomere lengthening. We found that RIF1 mutants that block Protein Phosphatase 1 (PP1) binding activated telomeric origins but did not elongate telomeres. In a second approach, we found overexpression of ∆N-Dbf4 and Cdc7 increased DDK activity and activated telomeric origins, yet telomere length was unchanged. We tested a third mechanism to activate origins using the sld3-A mcm5-bob1 mutant that de-regulates the pre-replication complex, and again saw no change in telomere length. Finally, we tested whether mutations in RIF1 that cause telomere elongation would affect origin firing. We found that neither rif1-∆1322 nor rif1HOOK affected firing of telomeric origins. We conclude that telomeric origin firing does not cause telomere elongation, and the role of Rif1 in regulating origin firing is separable from its role in regulating telomere length.

scholarly journals Swc4 positively regulates telomere length independently of its roles in NuA4 and SWR1 complexes

2020 ◽  
Vol 48 (22) ◽  
pp. 12792-12803
Author(s):  
Jia-Cheng Liu ◽  
Qian-Jin Li ◽  
Ming-Hong He ◽  
Can Hu ◽  
Pengfei Dai ◽  
...  
Keyword(s):  
Telomere Length ◽  
Essential Gene ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Direct Role ◽  
Telomere Shortening ◽  
Length Regulation ◽  
Telomere Length Regulation

Abstract Telomeres at the ends of eukaryotic chromosomes are essential for genome integrality and stability. In order to identify genes that sustain telomere maintenance independently of telomerase recruitment, we have exploited the phenotype of over-long telomeres in the cells that express Cdc13-Est2 fusion protein, and examined 195 strains, in which individual non-essential gene deletion causes telomere shortening. We have identified 24 genes whose deletion results in dramatic failure of Cdc13-Est2 function, including those encoding components of telomerase, Yku, KEOPS and NMD complexes, as well as quite a few whose functions are not obvious in telomerase activity regulation. We have characterized Swc4, a shared subunit of histone acetyltransferase NuA4 and chromatin remodeling SWR1 (SWR1-C) complexes, in telomere length regulation. Deletion of SWC4, but not other non-essential subunits of either NuA4 or SWR1-C, causes significant telomere shortening. Consistently, simultaneous disassembly of NuA4 and SWR1-C does not affect telomere length. Interestingly, inactivation of Swc4 in telomerase null cells accelerates both telomere shortening and senescence rates. Swc4 associates with telomeric DNA in vivo, suggesting a direct role of Swc4 at telomeres. Taken together, our work reveals a distinct role of Swc4 in telomere length regulation, separable from its canonical roles in both NuA4 and SWR1-C.

scholarly journals Regulating telomere length from the inside out: The replication fork model

2016 ◽  
Author(s):  
Carol W Greider
Keyword(s):  
Telomere Length ◽  
Alternative Model ◽  
Replication Fork ◽  
Molecular Level ◽  
Origin Firing ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Inside Out ◽  
Counting Model

Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease, thus it is important to understand the mechanisms that regulate length at the molecular level. The prevailing protein counting model for regulating telomerase access to elongate the telomere does not explain accumulating evidence of a role of DNA replication in telomere length regulation. Here I present an alternative model: the replication fork model that can explain how passage of a replication fork and regulation of origin firing affect telomere length.

Telomere length regulation during cloning, embryogenesis and ageing

2005 ◽  
Vol 17 (2) ◽  
pp. 85 ◽  
Author(s):  
S. Schaetzlein ◽  
K. L. Rudolph
Keyword(s):  
Telomere Length ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Postnatal Life ◽  
Bovine Embryos ◽  
Telomeric Dna ◽  
Cell Therapies ◽  
Telomere Elongation ◽  
Length Regulation ◽  
Cloned Bovine

Telomeres are nucleoprotein complexes at the end of eukaryotic chromosomes with an essential role in chromosome capping. Owing to the end-replication problem of DNA polymerase, telomeres shorten during each cell division. When telomeres become critically short, they loose their capping function, which in turn induces a DNA damage-like response. This mechanism inhibits cell proliferation at the senescence stage and there is evidence that it limits the regenerative capacity of tissues and organs during chronic diseases and ageing. The holoenzyme telomerase synthesises telomeric DNA de novo, but, in humans, it is active only during embryogenesis, in immature germ cells and in a subset of stem/progenitor cells during postnatal life. Telomere length can be maintained or increased by telomerase, a process that appears to be regulated by a variety of telomere-binding proteins that control telomerase recruitment and activity at the telomeres. During embryogenesis, telomerase is strongly activated at the morula/blastocyst transition. At this transition, telomeres are significantly elongated in murine and bovine embryos. Early embryonic telomere elongation is telomerase dependent and leads to a rejuvenation of telomeres in cloned bovine embryos. Understanding of the molecular mechanisms underlying this early embryonic telomere elongation programme is of great interest for medical research in the fields of regeneration, cell therapies and therapeutic cloning.

scholarly journals Chromosome specific telomere lengths and the minimal functional telomere revealed by nanopore sequencing

2021 ◽  
Author(s):  
Samantha L. Sholes ◽  
Kayarash Karimian ◽  
Ariel Gershman ◽  
Thomas J. Kelly ◽  
Winston Timp ◽  
...  
Keyword(s):  
Telomere Length ◽  
Clonal Variation ◽  
Nanopore Sequencing ◽  
Biological Mechanisms ◽  
Specific Chromosome ◽  
Telomere Shortening ◽  
Long Read ◽  
Length Regulation ◽  
Telomere Length Regulation

We developed a method to tag telomeres and measure telomere length by nanopore sequencing in the yeast S. cerevisiae. Nanopore allows long read sequencing through the telomere, subtelomere and into unique chromosomal sequence, enabling assignment of telomere length to a specific chromosome end. We observed chromosome end specific telomere lengths that were stable over 120 cell divisions. These stable chromosome specific telomere lengths may be explained by stochastic clonal variation or may represent a new biological mechanism that maintains equilibrium unique to each chromosomes end. We examined the role of RIF1 and TEL1 in telomere length regulation and found that TEL1 is epistatic to RIF1 at most telomeres, consistent with the literature. However, at telomeres that lack subtelomeric Y' sequences, tel1Δ rif1Δ double mutants had a very small, but significant, increase in telomere length compared to the tel1Δ single mutant, suggesting an influence of Y' elements on telomere length regulation. We sequenced telomeres in a telomerase-null mutant (est2Δ) and found the minimal telomere length to be around 75bp. In these est2Δ mutants there were many apparent telomere recombination events at individual telomeres before the generation of survivors, and these events were significantly reduced in est2Δ rad52Δ double mutants. The rate of telomere shortening in the absence of telomerase was similar across all chromosome ends at about 5 bp per generation. This new method gives quantitative, high resolution telomere length measurement at each individual chromosome end, suggests possible new biological mechanisms regulating telomere length, and provides capability to test new hypotheses.

scholarly journals Tel1 Activation by the MRX Complex Is Sufficient for Telomere Length Regulation but Not for the DNA Damage Response in Saccharomyces cerevisiae

Genetics ◽  
2019 ◽  
Vol 213 (4) ◽  
pp. 1271-1288 ◽  
Author(s):  
Rebecca Keener ◽  
Carla J. Connelly ◽  
Carol W. Greider
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Telomere Length ◽  
Dna Damage Response ◽  
Telomere Elongation ◽  
Link Type ◽  
Epistasis Analysis ◽  
Damage Response ◽  
Length Regulation ◽  
Telomere Length Regulation

Previous models suggested that regulation of telomere length in Saccharomyces cerevisiae by Tel1(ATM) and Mec1(ATR) would parallel the established pathways regulating the DNA damage response. Here, we provide evidence that telomere length regulation differs from the DNA damage response in both the Tel1 and Mec1 pathways. We found that Rad53 mediates a Mec1 telomere length regulation pathway but is dispensable for Tel1 telomere length regulation, whereas in the DNA damage response, Rad53 is regulated by both Mec1 and Tel1. Using epistasis analysis with a Tel1 hypermorphic allele, Tel1-hy909, we found that the MRX complex is not required downstream of Tel1 for telomere elongation but is required downstream of Tel1 for the DNA damage response. Our data suggest that nucleolytic telomere end processing is not a required step for telomerase to elongate telomeres.

scholarly journals The Mre11p/Rad50p/Xrs2p Complex and the Tel1p Function in a Single Pathway for Telomere Maintenance in Yeast

Genetics ◽  
2000 ◽  
Vol 155 (1) ◽  
pp. 475-479 ◽  
Author(s):  
Kim B Ritchie ◽  
Thomas D Petes
Keyword(s):  
Telomere Length ◽  
Complex Function ◽  
Telomere Maintenance ◽  
Nonhomologous End Joining ◽  
Dna Breaks ◽  
End Joining ◽  
Epistasis Analysis ◽  
Double Strand Dna Breaks ◽  
Length Regulation ◽  
Telomere Length Regulation

Abstract The Mre11p/Rad50p/Xrs2p complex is involved in the repair of double-strand DNA breaks, nonhomologous end joining, and telomere length regulation. TEL1 is primarily involved in telomere length regulation. By an epistasis analysis, we conclude that Tel1p and the Mre11p/Rad50p/Xrs2p complex function in a single pathway of telomere length regulation.

scholarly journals Mechanistic Model of Telomere Length Homeostasis in Yeast

2021 ◽  
Author(s):  
Ghanendra Singh ◽  
Sriram K
Keyword(s):  
Telomere Length ◽  
Molecular Mechanisms ◽  
Global Analysis ◽  
Mechanistic Model ◽  
Stochastic Simulations ◽  
Phase Plane Analysis ◽  
Plane Analysis ◽  
Length Regulation ◽  
Telomere Length Homeostasis

Cells maintain homeostatic telomere length, and this homeostatic disruption leads to various types of diseases. Presently, it is not clear how telomeres achieve homeostasis. One of the prevailing hypotheses is a protein-counting model with a built-in sensor mechanism that counts proteins that directly regulate the telomeric length. However, it does not explain telomere length regulation at the mechanistic level. Here, we present a mathematical model based on the underlying molecular mechanisms of length regulation needed to establish telomere length homeostasis in yeast. We perform both deterministic and stochastic simulations to validate the models with the experimental data of Teixeira et al., rate-balance plot, and phase plane analysis to understand the nature of dynamics exhibited by the models. For global analysis, we constructed bifurcation diagrams. The model explains the role of negative and positive feedback loops and a delay between telomerase and telomere-bound proteins, leading to oscillations in telomere length. We map these in-silico results to proposition by Teixeira of telomeres making a transition between extendible and non-extendible states.

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