Telomere Lengthening and Other Functions of Telomerase

Rubtsova, Maria P.; Vasilkova, Daria; Malyavko, Alexander N.; Naraikina, Yu. V.; Zvereva, Maria I.; Донцова, О. А.

doi:10.32607/20758251-2012-4-2-44-61

Cited by 46 publications

(13 citation statements)

References 183 publications

(223 reference statements)

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“…The maintenance of telomere length is a major molecular factor in human cancer development. Unlimited replication and immortalization are key features of neoplastic cells, needed to escape replicative senescence due to telomere shortening [ 41 , 47 ]. Telomere length can be maintained via two different mechanisms: (i) reactivation of telomerase reverse transcriptase (TERT) via promoter mutations or methylation; and (ii) a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT), which relies on the homologous recombination of telomeric regions [ 1 , 2 , 5 , 19 , 20 , 26 , 38 ], and results in a heterogeneous length and sequence composition [ 19 , 20 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

et al. 2020

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Purpose The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined. Methods We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR. Results Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length. Conclusion Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.

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Section: Introductionmentioning

confidence: 99%

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

et al. 2020

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“…Unexpectedly, tissues of the long-lived strains were also characterized by an up-regulated TERT subunit of telomerase, which appeared to be unable to prevent the age-related shortening of telomeres [ 118 ]. This may suggest that DNA damage responsible for DNA shortening exceeded the repair capacity of telomerase or that telomerase exerts some alternative, telomere length-independent functions in N. furzeri [ 119 ]. In N. guentheri , in turn, there was no change in telomerase activity with age [ 103 ].…”

Section: Aging In the Fish Of The Genus Nothobranchiusmentioning

confidence: 99%

Nontraditional systems in aging research: an update

Mikuła-Pietrasik

Pakuła

Markowska

et al. 2020

Cell. Mol. Life Sci.

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Research on the evolutionary and mechanistic aspects of aging and longevity has a reductionist nature, as the majority of knowledge originates from experiments on a relatively small number of systems and species. Good examples are the studies on the cellular, molecular, and genetic attributes of aging (senescence) that are primarily based on a narrow group of somatic cells, especially fibroblasts. Research on aging and/or longevity at the organismal level is dominated, in turn, by experiments on Drosophila melanogaster, worms (Caenorhabditis elegans), yeast (Saccharomyces cerevisiae), and higher organisms such as mice and humans. Other systems of aging, though numerous, constitute the minority. In this review, we collected and discussed a plethora of up-to-date findings about studies of aging, longevity, and sometimes even immortality in several valuable but less frequently used systems, including bacteria (Caulobacter crescentus, Escherichia coli), invertebrates (Turritopsis dohrnii, Hydra sp., Arctica islandica), fishes (Nothobranchius sp., Greenland shark), reptiles (giant tortoise), mammals (blind mole rats, naked mole rats, bats, elephants, killer whale), and even 3D organoids, to prove that they offer biogerontologists as much as the more conventional tools. At the same time, the diversified knowledge gained owing to research on those species may help to reconsider aging from a broader perspective, which should translate into a better understanding of this tremendously complex and clearly system-specific phenomenon.

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“…The Tep1 and Terf1 genes involved in telomere length regulation belong to the set of positively selected genes in NMR, unlike those in the rat and mouse [23]. Telomere length is short in NMR: the telomeres are shorter than those in laboratory mice or rats and are approximately as long as human telomeres.…”

Section: Studying the Nmr Genome And Transcriptome Using Bioinformatimentioning

confidence: 99%

Genome Stability Maintenance in Naked Mole-Rat

Petruseva¹,

Evdokimov²,

Lavrik³

2017

Acta Naturae

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The naked mole-rat (Heterocephalus glaber) is one of the most promising models used to study genome maintenance systems, including the effective repair of damage to DNA. The naked mole-rat is the longest lived rodent species, which is extraordinarily resistant to cancer and has a number of other unique phenotypic traits. For at least 80% of its lifespan, this animal shows no signs of aging or any increased likelihood of death and retains the ability to reproduce. The naked mole-rat draws the heightened attention of researchers who study the molecular basis of lengthy lifespan and cancer resistance. Despite the fact that the naked mole-rat lives under genotoxic stress conditions (oxidative, etc.), the main characteristics of its genome and proteome are a high stability and effective functioning. Replicative senescence in the somatic cells of naked mole-rats is missing, while an additional p53/pRb-dependent mechanism of early contact inhibition has been revealed in its fibroblasts, which controls cell proliferation and its mechanism of arf-dependent aging. The unique traits of phenotypic and molecular adaptations found in the naked mole-rat speak to a high stability and effective functioning of the molecular machinery that counteract damage accumulation in its genome. This review analyzes existing results in the study of the molecular basis of longevity and high cancer resistance in naked mole-rats.

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Telomere Lengthening and Other Functions of Telomerase

Cited by 46 publications

References 183 publications

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

Nontraditional systems in aging research: an update

Genome Stability Maintenance in Naked Mole-Rat

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