Telomeres: protecting chromosomes against genome instability

O’Sullivan, Roderick J.; Karlseder, Jan

doi:10.1038/nrm2848

Cited by 810 publications

(614 citation statements)

References 122 publications

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“…3,4 Telomeres function primarily to mask double-strand break DNA damage signals at chromosomal termini, inhibit terminal exonucleolytic degradation, and prevent chromosomal fusions. 5,6 In normal somatic cells, telomeres shorten with each cell division, and significant telomere shortening leads to p53-dependent senescence or apoptosis. 7 As a result, there is a limited number of population doublings that a somatic cell lineage may undergo, at which point further proliferative expansion is blocked.…”

mentioning

confidence: 99%

Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer Subtypes

Heaphy

Subhawong

Hong

et al. 2011

The American Journal of Pathology

433

455

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Approximately 10% to 15% of human cancers lack detectable telomerase activity, and a subset of these maintain telomere lengths by the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in subtypes of sarcomas and astrocytomas, has rarely been reported in epithelial malignancies. However, the prevalence of ALT has not been thoroughly assessed across all cancer types. We therefore comprehensively surveyed the ALT phenotype in a broad range of human cancers. In total, two independent sets comprising 6110 primary tumors from 94 different cancer subtypes, 541 benign neoplasms, and 264 normal tissue samples were assessed by combined telomere-specific fluorescence in situ hybridization and immunofluorescence labeling for PML protein. Overall, ALT was observed in 3.73% (228/6110) of all tumor specimens, but was not observed in benign neoplasms or normal tissues. This is the first report of ALT in carcinomas arising from the bladder, cervix, endometrium, esophagus, gallbladder, kidney, liver, and lung. Additionally, this is the first report of ALT in medulloblastomas, oligodendrogliomas, meningiomas, schwannomas, and pediatric glioblastoma multiformes. Previous studies have shown associations between ALT status and prognosis in some tumor types; thus, further studies are warranted to assess the potential prognostic significance and unique biology of ALT-positive tumors. These findings may have therapeutic consequences, because ALT-positive cancers are predicted to be resistant to anti-telomerase therapies.

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mentioning

confidence: 99%

Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer Subtypes

Heaphy

Subhawong

Hong

et al. 2011

The American Journal of Pathology

433

455

View full text Add to dashboard Cite

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“…Telomeres are repetitive G-rich DNA-protein complexes that cap the ends of eukaryotic chromosomes and play essential roles in preventing the activation of DNA damage checkpoints that would otherwise induce cellular senescence and/or apoptosis [11]. Maintenance of telomere function requires the enzyme telomerase and shelterin, a complex of six proteins required to prevent telomeres from inappropriately activating the DNA damage checkpoint function.…”

Section: Introductionmentioning

confidence: 99%

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

et al. 2013

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The INO80 (inositol requiring mutant 80) chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mIno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mIno80. Deletion of mIno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mIno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of γ-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response. mIno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair (HDR) at telomeres. Fragile telomeres were prominent in mIno80 ∆/∆ MEFs, suggesting that chromatin remodeling is required for efficient telomere replication. mIno80 −/− mouse embryos die early during embryogenesis, while conditional deletion of mIno80 in adult mice results in weight loss and premature death. In a p53 −/− tumorprone background, mIno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dysfunctional telomeres, and maintenance of genome stability.

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“…In sexually reproducing animals such as humans, telomere elongation occurs mainly during embryogenesis and the development of the germ line (7,8). Somatic cells become senescent in the adult when chromosome ends shorten to a critical length to avoid deleterious genome instability and the emergence of cancerous cells (9). This protective senescence mechanism appears to be a central part of the aging process (10), and animals that are potentially immortal must have somatic mechanisms for maintaining chromosome ends.…”

mentioning

confidence: 99%

Telomere maintenance and telomerase activity are differentially regulated in asexual and sexual worms

Tan

Rahman

Jaber-Hijazi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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In most sexually reproducing animals, replication and maintenance of telomeres occurs in the germ line and during early development in embryogenesis through the use of telomerase. Somatic cells generally do not maintain telomere sequences, and these cells become senescent in adults as telomeres shorten to a critical length. Some animals reproduce clonally and must therefore require adult somatic mechanisms for maintaining their chromosome ends. Here we study the telomere biology of planarian flatworms with apparently limitless regenerative capacity fueled by a population of highly proliferative adult stem cells. We show that somatic telomere maintenance is different in asexual and sexual animals. Asexual animals maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual animals only achieve telomere elongation through sexual reproduction. We demonstrate that this difference is reflected in the expression and alternate splicing of the protein subunit of the telomerase enzyme. Asexual adult planarian stem cells appear to maintain telomere length over evolutionary timescales without passage through a germ-line stage. The adaptations we observe demonstrate indefinite somatic telomerase activity in proliferating stem cells during regeneration or reproduction by fission, and establish planarians as a pertinent model for studying telomere structure, function, and maintenance.

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Telomeres: protecting chromosomes against genome instability

Cited by 810 publications

References 122 publications

Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer Subtypes

Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer Subtypes

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

Telomere maintenance and telomerase activity are differentially regulated in asexual and sexual worms

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