Telomeres in cancer: tumour suppression and genome instability

Maciejowski, John; Lange, Titia de

doi:10.1038/nrm.2016.171

Cited by 583 publications

(531 citation statements)

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“…Some cells survive crisis by acquiring the ability to maintain telomeres. However, these survivors contain chromosome fusions formed during crisis through A-NHEJ, which have been shown to be involved in tumor development (Rai et al, 2010;Jones et al, 2014;Maciejowski and de Lange, 2017). Similarly, chromosome fusions as a consequence of telomere loss in tumor cells expressing telomerase also appear to involve A-NHEJ (Fouladi et al, 2000;Lo et al, 2002b).…”

Section: The Sensitivity Of Subtelomeric Regions To Double-strand Breaksmentioning

confidence: 99%

“…In addition to BFB cycles, in some cases, fused chromosomes can also undergo catastrophic shattering near telomeres, called chromothripsis (Maciejowski et al, 2015; reviewed by Maciejowski and de Lange, 2017). When dicentric chromosomes are formed, they persist through mitosis and cytokinesis, and long chromatin bridges between daughter cells are formed, which disrupts the formation of a nuclear envelope.…”

Section: The Sensitivity Of Subtelomeric Regions To Double-strand Breaksmentioning

confidence: 99%

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The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Muraki

Murnane

2017

Genes Genet. Syst.

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In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini. Telomeres and subtelomeric regions are poor substrates for DNA replication; therefore, regions near telomeres are prone to replication fork stalling and chromosome breakage. Moreover, DSBs near telomeres are poorly repaired. As a result, when DSBs occur near telomeres in normal cells, the cells stop proliferating, while in cancer cells, subtelomeric DSBs induce rearrangements due to the absence of cell cycle checkpoints. The sensitivity of subtelomeric regions to DSBs is due to the improper regulation of processing, because although C-NHEJ is functional at subtelomeric DSBs, excessive processing results in an increased frequency of large deletions and chromosome rearrangements involving A-NHEJ.

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Section: The Sensitivity Of Subtelomeric Regions To Double-strand Breaksmentioning

confidence: 99%

Section: The Sensitivity Of Subtelomeric Regions To Double-strand Breaksmentioning

confidence: 99%

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Muraki

Murnane

2017

Genes Genet. Syst.

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“…(96) Revealing these networks by constructing a model of interaction between telomeres, stem cells and mitochondria will provide us advance biomarkers for aging and the strategies for therapy, i.e., telomeres stabilization either through brief telomerase reactivation, p53 modulation, mitochondrial function and biogenesis improvement, and mechanistic target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K) pathways modulation, to rejuvenate both proliferating and quiescent the aged tissues. (96) in approximately 90% of all malignant tumors (52), may predict poor or favorable outcome (110,111), thus making telomerase both a highly attractive biomarker and target for the development of mechanism-based cancer diagnostics, prognostics, and therapeutics. (30) Genome instability caused by telomere crisis was found to induce chromosome gains and loses (aneuploidy), translocations, gene loss (manifested as loss of heterozygosity (LOH)) and regional amplification through BFB cycles ( Figure 6).…”

Section: Telomeres and Cancermentioning

confidence: 99%

Telomere in Aging and Age-Related Diseases

2017

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B ACKGROUND:The number of elderly population in the world keep increasing. In their advanced ages, many elderly face years of disability because of multiple chronic diseases, frailty, making them lost their independence. Consequently, this could have impacts on social and economic stability. A huge challenge has been sent for biomedical researchers to compress or at least eliminate this period of disability and increase the health span. CONTENT:Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human diseases. Accelerated telomere erosion was clearly correlated with a pack of metabolic and inflammatory diseases. Critically short telomeres or the unprotected end, are likely to form telomeric fusion, generating genomic Abstract R E V I E W A R T I C L Einstability, the cornerstone for carcinogenesis. Enlightening how telomeres involved in the mechanisms underlying the diseases' pathogenesis was expected to uncover new molecular targets for any important diagnosis or therapeutic implications. SUMMARY:Telomere shortening was foreseen as an imporant mechanism to supress tumor by limiting cellular proliferative capacity by regulating senescence check point activation. Many human diseases and carcinogenesis are causally related to defective telomeres, asserting the importance of telomeres sustainment. Thus, telomere length assessment might serve as an important tool for clinical prognostic, diagnostic, monitoring and management.

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“…Telomeres are nucleoprotein structures assembled at the ends of eukaryotic chromosomes which protect chromosome ends from being recognized as sites of DNA damage [1]. For this reason, telomeres are essential to genome integrity.…”

Section: Introductionmentioning

confidence: 99%

“…Telomeric repeats are bound by a set of telomere-binding proteins, known as the “shelterin” complex in mammalian cells, which mediate telomere function by preventing the activation of the DNA damage response. Shelterin thus functions to impede the induction of DNA repair mechanisms at chromosome ends, including non-homologous end joining (NHEJ) and homologous recombination (HR), which could lead to chromosome end fusions and genome instability [1]. …”

Section: Introductionmentioning

confidence: 99%

Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells

et al. 2018

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Telomeres cap the ends of eukaryotic chromosomes, protecting them from degradation and erroneous recombination events which may lead to genome instability. Telomeres are transcribed giving rise to telomeric repeat-containing RNAs, called TERRA. The TERRA long noncoding RNAs have been proposed to play important roles in telomere biology, including heterochromatin formation and telomere length homeostasis. While TERRA RNAs are predominantly nuclear and localize at telomeres, little is known about the dynamics and function of TERRA molecules expressed from individual telomeres. Herein, we developed an assay to image endogenous TERRA molecules expressed from a single telomere in living human cancer cells. We show that single-telomere TERRA can be detected as TERRA RNA single particles which freely diffuse within the nucleus. Furthermore, TERRA molecules aggregate forming TERRA clusters. Three-dimensional size distribution and single particle tracking analyses revealed distinct sizes and dynamics for TERRA RNA single particles and clusters. Simultaneous time lapse confocal imaging of TERRA particles and telomeres showed that TERRA clusters transiently co-localize with telomeres. Finally, we used chemically modified antisense oligonucleotides to deplete TERRA molecules expressed from a single telomere. Single-telomere TERRA depletion resulted in increased DNA damage at telomeres and elsewhere in the genome. These results suggest that single-telomere TERRA transcripts participate in the maintenance of genomic integrity in human cancer cells.

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Telomeres in cancer: tumour suppression and genome instability

Cited by 583 publications

References 178 publications

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Telomere in Aging and Age-Related Diseases

Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells

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