Modification of Subtelomeric DNA

Steinert, Susanne; Shay, Jerry W.; Wright, Woodring E.

doi:10.1128/mcb.24.10.4571-4580.2004

Cited by 64 publications

(46 citation statements)

References 35 publications

(42 reference statements)

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“…In particular, both telomeres and subtelomeres are enriched in histone marks characteristic of constitutive heterochromatin, including trimethylated H4K20 and H3K9, as well as are bound by the heterochromatin protein 1 isoforms (HP1a, HP1b and HP1g) (Garcı´a-Cao et al, 2004;Gonzalo et al, , 2006Benetti et al, 2007b;reviewed in Blasco, 2007). In addition, subtelomeric DNA repeats are heavily methylated both in humans and mice (Steinert et al, 2004;Fraga et al, 2005;Gonzalo et al, 2006). These epigenetic marks at telomeres and subtelomeres are characteristic of a compacted chromatin state, and have been demonstrated to act as negative regulators of telomere length.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of telomeres in human cancer

et al. 2008

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Hypomethylation of repeated elements in the genome is a common feature of human cancer, however, the direct consequences of this epigenetic defect for cancer biology are still largely unknown. Telomeres are specialized chromatin structures at the ends of eukaryotic chromosomes formed by tandem repeats of G-rich sequences and associated proteins, which have an essential role in chromosome end protection and genomic stability. Telomeric DNA repeats cannot be methylated, however, the adjacent subtelomeric DNA is heavily methylated in humans. Here, we show that the methylation status of subtelomeric DNA repeats negatively correlates with telomere length and telomere recombination in a large panel of human cancer cell lines. These findings suggest that tumor telomere length and integrity can be influenced by epigenetic factors. Finally, we show that treatment of human cancer cell lines with demethylating drugs results in hypomethylation of subtelomeric repeats and increased telomere recombination, which in turn may facilitate telomere elongation. All together, these findings suggest that tumor telomere length and integrity can be influenced by the epigenetic status of cancer cells.

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Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of telomeres in human cancer

et al. 2008

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“…11 Similar to pericentromeric regions, subtelomeres have a high density of DNA repeats and CpG islands, which are susceptible to DNA methylation by DNA methyltransferases (DNMTs). 12,13 Telomeres, however, do not contain CpG sequences.…”

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confidence: 99%

Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis

Choi

et al. 2010

Intl Journal of Cancer

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Subtelomeric chromatin modifications are important regulators of telomere length. We examined the subtelomeric DNA methylation status of 7q, 8q, 17q, 18p, 21q and XpYp in 32 pairs of hepatocellular carcinomas (HCCs) and their adjacent nonHCCs via methylation-specific PCR (quantified as methylation ratio). In addition, 10q was subjected to bisulfite-genomicsequencing. Telomere length was determined by Southern hybridization. In all cases, the relationship between methylation ratio and telomere length was determined. High levels of methylation ratio were found on chromosomes 7q, 18p and XpYp, whereas 8q 17q and 21q were less methylated in both HCCs and non-HCCs. Compared to non-HCCs, HCCs exhibited a higher methylation ratio on 18p and 21q, and a wider distribution of methylation ratio on 7q, 21q and 10q (p < 0.05). The methylation ratio of 18p and of 21q was negatively and positively correlated with telomere length of HCCs, respectively (p < 0.05). We evaluated changes in methylation pattern between non-HCCs and HCCs. Out of 185 sites, hypermethylation changes from non-HCC to HCC were found at 47 sites and hypomethylation changes at 31 sites. Changes in methylation pattern were observed at three to four sites among six chromosomal sites in 15 patients (47%). There was a tendency toward hypomethylation changes at 7q (p 5 0.013) and hypermethylation changes at 21q (p 5 0.057) when telomere lengthened from non-HCCs to HCCs. In summary, subtelomeric methylation patterns dynamically changed during hepatocarcinogenesis. Subtelomeric methylation at certain regions was related to telomere lengthening or shortening, suggesting an association between subtelomeric chromatin structure and telomere length regulation in human hepatocarcinogenesis.

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“…Currently relatively little is known about epigenetic modification of telomeric or subtelomeric DNA in human cells although one study of the human Xp/Yp telomere indicated that a region immediately adjacent to the telomere is modified in some way but not just by CpG methylation (Steinert et al, 2004). In another study it was shown that subtelomeric regions were hypomethylated in human ICF cells that have reduced DNMT3B.…”

Section: Chromatin and Altmentioning

confidence: 96%

Telomere length maintenance – an ALTernative mechanism

Royle

Foxon

Jeyapalan

et al. 2008

Cytogenet Genome Res

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The Alternative Lengthening of Telomeres (ALT) mechanism is utilised by approximately 10% of human tumours and a higher proportion of some types of sarcomas. ALT+ cell lines and tumours show heterogeneous telomere length, extra-chromosomal circular and linear telomeric DNA, ALT associated promyelocytic bodies (APBs), a high frequency of post-replication exchanges in telomeres (designated as telomere-sister chromatid exchanges, T-SCE) and high instability at a GC-rich minisatellite, MS32 (D1S8). It is clear that there is a link between the minisatellite instability and the mechanism that underpins ALT, however currently the nature of this relationship is uncertain. Single molecule analysis of telomeric DNA from ALT+ cell lines and tumours has revealed complex telomere mutations that have not been seen in cell lines or tumours that express telomerase. These complex telomere mutations cannot be explained by T-SCE but must arise by another inter-molecular process. The break-induced replication (BIR) model that may explain the observed high frequency of T-SCE and the presence of complex telomere mutations is reviewed.

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Modification of Subtelomeric DNA

Cited by 64 publications

References 35 publications

Epigenetic regulation of telomeres in human cancer

Epigenetic regulation of telomeres in human cancer

Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis

Telomere length maintenance – an ALTernative mechanism

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