Human telomeres replicate using chromosome-specific, rather than universal, replication programs

Drosopoulos, William C.; Kosiyatrakul, Settapong T.; Yan, Zi; Calderano, Simone Guedes; Schildkraut, Carl L.

doi:10.1083/jcb.201112083

Cited by 73 publications

(74 citation statements)

References 49 publications

(89 reference statements)

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“…Both results suggest that the subtelomeric region is important for controlling telomere replication timing, and, thus, a regulatory factor may be located within this specific region. This hypothesis is supported by a recent study that showed that the initiation of telomere replication occurs predominantly within the subtelomere or a region upstream of the subtelomere37. Our study confirms the role of subtelomere sequences in regulating telomere replication timing and furthermore, strongly supports the conclusion that neither centromeres nor other chromosomal sequences play a role in this process, and finally, that subtelomere sequences may be sufficient to determine telomere replication timing.…”

Section: Discussionsupporting

confidence: 89%

Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres

Piqueret-Stephan

Ricoul

Hempel

et al. 2016

Sci Rep

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Telomeres are specific structures that protect chromosome ends and act as a biological clock, preventing normal cells from replicating indefinitely. Mammalian telomeres are replicated throughout S-phase in a predetermined order. However, the mechanism of this regulation is still unknown. We wished to investigate this phenomenon under physiological conditions in a changing environment, such as the immortalization process to better understand the mechanism for its control. We thus examined the timing of human telomere replication in normal and SV40 immortalized cells, which are cytogenetically very similar to cancer cells. We found that the timing of telomere replication was globally conserved under different conditions during the immortalization process. The timing of telomere replication was conserved despite changes in telomere length due to endogenous telomerase reactivation, in duplicated homologous chromosomes, and in rearranged chromosomes. Importantly, translocated telomeres, possessing their initial subtelomere, retained the replication timing of their homolog, independently of the proportion of the translocated arm, even when the remaining flanking DNA is restricted to its subtelomere, the closest chromosome-specific sequences (inferior to 500 kb). Our observations support the notion that subtelomere regions strongly influence the replication timing of the associated telomere.

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Section: Discussionsupporting

confidence: 89%

Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres

Piqueret-Stephan

Ricoul

Hempel

et al. 2016

Sci Rep

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“…This observation implies that in some cases initiation of DNA replication occurs at the telomeres. Similar observations have been reported for telomeric DNA in Xenopus cell free extracts [49] and specific telomeres of individual human chromosomes in embryonic stem (ES) cell lines and two primary somatic cell types [50]. No bubble arc was observed for the 3284 bp PvuI-PvuI DNA fragment hybridized with L2 (see Figures 1 and 5), indicating that replication does not initiate at telomeric repeats in the circular pYAC_MEM.…”

Section: Discussionsupporting

confidence: 82%

Topoisomerase 2 Is Dispensable for the Replication and Segregation of Small Yeast Artificial Chromosomes (YACs)

et al. 2014

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DNA topoisomerases are thought to play a critical role in transcription, replication and recombination as well as in the condensation and segregation of sister duplexes during cell division. Here, we used high-resolution two-dimensional agarose gel electrophoresis to study the replication intermediates and final products of small circular and linear minichromosomes of Saccharomyces cerevisiae in the presence and absence of DNA topoisomerase 2. The results obtained confirmed that whereas for circular minichromosomes, catenated sister duplexes accumulated in the absence of topoisomerase 2, linear YACs were able to replicate and segregate regardless of this topoisomerase. The patterns of replication intermediates for circular and linear YACs displayed significant differences suggesting that DNA supercoiling might play a key role in the modulation of replication fork progression. Altogether, this data supports the notion that for linear chromosomes the torsional tension generated by transcription and replication dissipates freely throughout the telomeres.

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“…Telomerase is predicted to be recruited to backtracked replication forks resulting from stalling, which has been proposed to occur at measurable frequencies in telomeric DNA (Miller et al, 2006; Drosopoulos et al, 2012). Such backtracked forks will expose single-stranded leading strand TG (1-3) repeat sequence DNA, which is the substrate for telomerase elongation.…”

Section: Discussionmentioning

confidence: 99%

“…Telomeres are composed of sequence-specific DNA binding proteins bound to highly repetitive DNA sequences and are increasingly recognized as genomic regions prone to replication stress (Miller et al, 2006; Sfeir et al, 2009; Drosopoulos et al, 2012). Without the telomeric DNA-elongating enzyme telomerase, progressive telomere shortening eventually causes the collapse of the protective DNA-protein complex (deprotection), but this occurs only after many cell divisions, L ate after T elomerase I nactivation (LTI).…”

Section: Introductionmentioning

confidence: 99%

Early Telomerase Inactivation Accelerates Aging Independently of Telomere Length

Xie

Jay

Smith

et al. 2015

Cell

108

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SUMMRAY Telomerase is required for long-term telomere maintenance and protection. Using single budding yeast mother cell analyses we found that, even Early after Telomerase Inactivation (ETI), yeast mother cells show transient DNA Damage Response (DDR) episodes, stochastically altered cell cycle dynamics, and accelerated mother cell aging. The acceleration of ETI mother cell aging was not explained by increased reactive oxygen species (ROS), Sir protein perturbation, or deprotected telomeres. ETI occurred well before the population senescence and caused late after telomerase inactivation (LTI). ETI phenotypes were morphologically distinct from LTI senescence, genetically uncoupled from telomere length, and were rescued by elevating dNTP pools. Our combined genetic and single-cell analyses show that well before critical telomere shortening, telomerase is continuously required to respond to transient DNA replication stress in mother cells, and that a lack of telomerase accelerates otherwise normal aging.

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Human telomeres replicate using chromosome-specific, rather than universal, replication programs

Abstract: Human telomere replication initiates either from within telomere repeats or from within the subtelomere using a chromosome-specific replication program that appears conserved between different cell types.

Cited by 73 publications

References 49 publications

Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres

Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres

Topoisomerase 2 Is Dispensable for the Replication and Segregation of Small Yeast Artificial Chromosomes (YACs)

Early Telomerase Inactivation Accelerates Aging Independently of Telomere Length

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