Segmental Polymorphisms in the Proterminal Regions of a Subset of Human Chromosomes

Der-Sarkissian, Héra; Vergnaud, Gilles; Borde, Yves-Marie; Thomas, Gilles; Londoño-Vallejo, J. Arturo

doi:10.1101/gr.322802

Cited by 32 publications

(34 citation statements)

References 32 publications

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“…For a better overview of subtelomeric loci, we analysed the methylation level of a 553-bp fragment of DNF92 minisatellite. The DNF92 sequence (accession number Y13543) not only represents the most distal segment of the proximal subtelomeric region found mainly at chromosomes 1 (1pter), 5 (5qter), 6 (6qter), 8 (8pter) and 17 (17qter) but also is detected at a lower frequency at eight other chromosome ends (Monfouilloux et al, 1998;Der-Sarkissian et al, 2002). This segment is separated from the telomeric tract by the distal subtelomeric region, which spans around 10 kb (Flint et al, 1997;Monfouilloux et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

et al. 2009

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Most human tumor cells acquire immortality by activating the expression of telomerase, a ribonucleoprotein that maintains stable telomere lengths at chromosome ends throughout cell divisions. Other tumors use an alternative mechanism of telomere lengthening (ALT), characterized by high frequencies of telomeric sister chromatid exchanges (T-SCEs). Mechanisms of ALT activation are still poorly understood, but recent studies suggest that DNA hypomethylation of chromosome ends might contribute to the process by facilitating T-SCEs. Here, we show that ALT/T-SCE high tumor cells display low DNAmethylation levels at the D4Z4 and DNF92 subtelomeric sequences. Surprisingly, however, the same sequences retained high methylation levels in ALT/T-SCE high SV40-immortalized fibroblasts. Moreover, T-SCE rates were efficiently reduced by ectopic expression of active telomerase in ALT tumor cells, even though subtelomeric sequences remained hypomethylated. We also show that hypomethylation of subtelomeric sequences in ALT tumor cells is correlated with genome-wide hypomethylation of Alu repeats and pericentromeric Sat2 DNA sequences. Overall, this study suggests that, although subtelomeric DNA hypomethylation is often coincident with the ALT process in human tumor cells, it is not required for T-SCE.

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Section: Resultsmentioning

confidence: 99%

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

et al. 2009

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“…Segmental polymorphisms have been found in humans 11,12 but none has been reported in inbred mouse strains. Our results indicate that large genomic segmental polymorphisms can be rapidly mapped using high-resolution BAC array comparative genomic hybridization.…”

mentioning

confidence: 98%

Genomic segmental polymorphisms in inbred mouse strains

Jiang

Mao

et al. 2004

Nat Genet

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“…To determine the nature of telomeric material present in APBs we looked for the presence of true chromosome end markers in association with APBs. We performed FISH experiments using two subtelomeric probes, ICRFc112-F151 and F7501, each specific for independently duplicated subtelomeric sequences distributed among several chromosome extremities and located at 10-20 kb from the telomeric tract (15) (Fig. S3A).…”

Section: Telomeres Are Not Randomly Distributed But Cluster Around Pmlmentioning

confidence: 99%

Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination

Drašković

Arnoult

Steiner

et al. 2009

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

142

125

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Promyelocytic leukemia (PML) bodies (also called ND10) are dynamic nuclear structures implicated in a wide variety of cellular processes. ALT-associated PML bodies (APBs) are specialized PML bodies found exclusively in telomerase-negative tumors in which telomeres are maintained by recombination-based alternative (ALT) mechanisms. Although it has been suggested that APBs are directly implicated in telomere metabolism of ALT cells, their precise role and structure have remained elusive. Here we show that PML bodies in ALT cells associate with chromosome ends forming small, spatially well-defined clusters, containing on average 2-5 telomeres. Using an innovative approach that gently enlarges PML bodies in living cells while retaining their overall organization, we show that this physical enlargement of APBs spatially resolves the single telomeres in the cluster, but does not perturb the potential of the APB to recruit chromosome extremities. We show that telomere clustering in PML bodies is cell-cycle regulated and that unique telomeres within a cluster associate with recombination proteins. Enlargement of APBs induced the accumulation of telomere-telomere recombination intermediates visible on metaphase spreads and connecting heterologous chromosomes. The strand composition of these recombination intermediates indicated that this recombination is constrained to a narrow time window in the cell cycle following replication. These data provide strong evidence that PML bodies are not only a marker for ALT cells but play a direct role in telomere recombination, both by bringing together chromosome ends and by promoting telomere-telomere interactions between heterologous chromosomes.ALT-associated PML bodies (APBs) ͉ alternative lengthening of telomeres (ALT) ͉ Herpes simplex virus ICP0 ͉ telomere clusters P ML (promyelocytic leukemia) nuclear bodies, which are present in most cells, have been extensively studied and a wealth of information concerning their composition, structure, dynamics and function is available (1). The PML protein is essential for the formation of PML bodies and provides the structural scaffold to which other proteins bind. Over 60 additional proteins have been localized to PML bodies spatially or temporally [see the information on PML bodies from the Nuclear Protein Database, (2)], and as a consequence, PML bodies have been implicated in the regulation of virtually every biological function including DNA damage responses.In immortal cells that maintain telomeres by recombinationbased alternative lengthening mechanisms (ALT), a special variety of PML bodies is found that, in addition to the proteins normally associated with PML bodies, contain telomeric DNA, telomerespecific proteins, and DNA recombination and repair proteins (3). The structure and the role of these ALT-associated PML bodies (APBs) are unknown. There is, however, a clear association between the presence of APBs and the utilization of ALT for telomere maintenance. However, in those studies disruptions of APBs have often been achiev...

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Segmental Polymorphisms in the Proterminal Regions of a Subset of Human Chromosomes

Cited by 32 publications

References 32 publications

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

Genomic segmental polymorphisms in inbred mouse strains

Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination

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