Abrupt telomere shortening in normal human fibroblasts

Vidaček, Nikolina Škrobot; Ćukušić, Andrea; Ivanković, Milena; Fulgosi, Hrvoje; Huzak, Miljenko; Smith, James R.; Rubelj, Ivica

doi:10.1016/j.exger.2010.01.009

Cited by 21 publications

(21 citation statements)

References 27 publications

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“…In this work, peaks consist of numerous telomeric signals grouped within 1 kb (7-8 kb) along with sporadic signals of much lower sizes ranging from very short telomeres (0.4 kb) to almost full length (Baird et al 2003). We propose that the observed smears in Southern-STELA may represent the bulk of these low incidence scattered telomere sizes, previously explained as occasional ATS (Baird et al 2003;Vidaček et al 2010;Rubelj and Vondraček 1999).…”

Section: Discussionmentioning

confidence: 85%

“…Earlier, a theoretical model for ATS had been proposed as an explanation for the sudden and stochastic onset of cell senescence that includes occasional loss of all telomeric repeats (Rubelj and Vondraček 1999;Vidaček et al 2010). Indeed, such a phenomenon has been observed with STELA (Baird et al 2003) and PNA Q-FISH analysis (Callén et al 2002), but neither method can observe eventual complete loss of telomeric repeats.…”

Section: Identification Of Unique Human Xp/yp Subtelomeric Sequence Fmentioning

confidence: 94%

“…For example, it has been shown that in cells of the same replicative age individual chromosomes have different telomere lengths (Britt-Compton et al 2006). Also, gradual telomere shortening that occurs with replication of somatic cells cannot explain the unpredictable and sudden onset of senescence at the level of individual cells (Vidaček et al 2010;Rubelj et al 2000). To explain this phenomena it has been proposed that gradual telomere shortening is superimposed with occasional abrupt telomere shortening (ATS) when the t-loop is destabilized or if misfolding occurs.…”

Section: Introductionmentioning

confidence: 98%

“…Therefore, as cell culture progresses subfractions of cells with reduced population doublings (PD) are generated. ATS provides a compelling explanation for the sudden and stochastic onset of senescence of individual cells described as Sudden Senescence Syndrome (Rubelj and Vondraček 1999;Vidaček et al 2010).…”

Section: Introductionmentioning

confidence: 99%

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Human Xp/Yp telomere analysis by Southern-STELA

et al. 2011

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Telomeres are specialized structures designed to protect the ends of linear chromosomes. They are dynamic structures such that in normal somatic cells they constantly shorten as cell division progresses. There is compelling evidence that telomere shortening leads to cell senescence, a process perceived as the main cause of aging in higher mammals. Therefore, the features of telomere shortening are of great importance in understanding cell senescence and aging in general. By identifying unique subtelomeric regions, large enough to produce strong chemiluminescent signals, we have provided a new tool for Southern blot analysis of individual human Xp/Yp telomeres. We extend these results with quantitative fluorescence in situ hybridization using peptide nucleic acid probe (PNA Q-FISH) analysis of telomeres on the Y chromosome. Our results demonstrates unequal shortening dynamics between the p and q telomeres.

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Section: Discussionmentioning

confidence: 85%

Section: Identification Of Unique Human Xp/yp Subtelomeric Sequence Fmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Human Xp/Yp telomere analysis by Southern-STELA

et al. 2011

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“…[72] Using reaction for amplification of telomeric circular DNA, which is ten times more sensitive than 2D gel electrophoresis, we were able to detect t-circles in normal human skin fibroblasts MJ90 and normal human lung fibroblasts IMR90. [77] Unlike in ALT U2OS cells where t-circles can easily be detected by 2D gel electrophoresis, [73,72] their low presence in human fibroblasts MJ90 showed that rapid telomere deletion is a rare event in normal cells. A rough estimate shows that only less than 0,005 % of telomeres can undergo abrupt shortening per one cell division in these cells which is below the level of detection of 2D gel electrophoresis.…”

Section: Role Of Extrachromosomal Circular Telomere Dna In Cell Senesmentioning

confidence: 99%

Extrachromosomal DNA in Genome (in)Stability – Role of Telomeres

Nanić¹,

Ravlić²,

Rubelj³

2016

Croat. Chem. Acta

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Eukaryotic genome consists of long linear chromosomes. It is complex in its content and has dynamic features. It mostly consists of non-coding DNA of various repeats, often prone to recombination including creation of extrachromosomal DNA which can be re-integrated into distant parts of the genome, often in different chromosome. These events are usually part of normal genome function enabling molecular response to changes in the cell or organism's environment and enabling their evolutionary development as well. These mechanisms also contribute to genome instability as in the case of abnormal immortalization like in cancer cells. Telomeres are among most important repetitive sequences, located at the end of linear chromosomes. They serve as guardians of genome stability but they also have dynamic features playing important role in cell aging and immortalization, both as chromosomal components or as extrachromosomal DNA. Also, recombination events on telomeres provide plausible explanation for stochastic nature of cell senescence, a phenomenon unjustly overlooked in broader literature.Keywords: extrachromosomal DNA, genome stability, satellite DNA, telomeres, cell aging. EUKARYO TIC GENOMEIZE of eukaryotic genomes often are not correlated with their genetic complexity. These differences do not come from significant variation in the number of genes but rather from content of several types of non-coding sequences that make large part of the genome. Although the number and the size of chromosomes differ between eukaryotic species, their basic structure is identical for all eukaryotes. The DNA and corresponding proteins in the interphase nucleus is called chromatin. The degree of chromatin condensation changes throughout the cell cycle. Part of the chromatin that is relaxed in the interphase is called euchromatin and mostly contains active genes. The remaining ∼ 10 % of the interphase chromatin represents heterochromatin which is condensed and transcriptionally suppressed because it mostly consists of highly repetitive DNA sequences. Thus, the structure of chromatin in eukaryotes is closely correlated with the control of gene expression.During the cell division the chromatin progressively condenses forming metaphase chromosomes, in which the DNA density increases up to 10 000 times. [1] THE REPETITIVE DNA CON TENT OF THE GENOME Repetitive sequences represent the most variable component which plays significant role in the complexity and dynamic of eukaryotic genomes. Approximately 50 % of the human genome is comprised of repetitive DNA. Types of repetitive sequences can be determined based on the kinetics of their reassociation upon denaturation. [2][3][4][5] Highly repetitive DNA represents ∼ 30 -45 % of mammalian DNA and reassociates quickly after denaturation. It consists of three subgroups of repetitive DNA. i) Satellite DNA is usually 100 kilo base (kb) to 1 mega base (mb) long and spans centromeric areas. In human genome, alphoid satellite DNA with 171 base pairs (bp) long repeats occupies 3 -5 % of the...

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Mutual interactions between telomere heterogeneity and cell culture growth dynamics shape stochasticity of cell aging

et al. 2017

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Mathematical modeling and computational simulations are often used to explain the stochastic nature of cell aging. The models published thus far are based on the molecular mechanisms of telomere biology and how they dictate the dynamics of cell culture proliferation. However, the influence of cell growth conditions on telomere dynamics has been widely overlooked. These conditions include interactions with surrounding cells through contact inhibition, gradual accumulation of non-dividing cells, culture propagation and other cell culture maintenance factors. In order to follow the intrinsic growth dynamics of normal human fibroblasts we employed the fluorescent dye DiI and FACS analysis which can distinguish cells that undergo different numbers of divisions within culture. We observed rapid generation of cell subpopulations undergoing from 0 to 9 divisions within growing cultures at each passage analyzed. These large differences in number of divisions among individual cells guarantee a strong impact on generation of telomere length heterogeneity in normal cell cultures and suggest that culture conditions should be included in future modeling of cell senescence.

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Abrupt telomere shortening in normal human fibroblasts

Cited by 21 publications

References 27 publications

Human Xp/Yp telomere analysis by Southern-STELA

Human Xp/Yp telomere analysis by Southern-STELA

Extrachromosomal DNA in Genome (in)Stability – Role of Telomeres

Mutual interactions between telomere heterogeneity and cell culture growth dynamics shape stochasticity of cell aging

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