The terminal DNA structure of mammalian chromosomes

McElligott, Richard; Wellinger, Raymund J.

doi:10.1093/emboj/16.12.3705

Cited by 320 publications

(225 citation statements)

References 56 publications

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“…All human telomeres carry a 3' overhang of several hundred nt of single-stranded TTAGGG repeats ( Figure 1A) (Hu man et al, 2000;Makarov et al, 1997;McElligott and Wellinger, 1997;Wright et al, 1997). It seems unlikely that telomeres with such a 3' protrusion would be a substrate for NHEJ.…”

Section: Cellular Consequences Of Telomere Dysfunction: Apoptosis Andmentioning

confidence: 99%

Protection of mammalian telomeres

2002

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Telomeres allow cells to distinguish natural chromosome ends from damaged DNA. When telomere function is disrupted, a potentially lethal DNA damage response can ensue, DNA repair activities threaten the integrity of chromosome ends, and extensive genome instability can arise. It is not clear exactly how the structure of telomere ends di ers from sites of DNA damage and how telomeres protect chromosome ends from DNA repair activities. What are the de®ning structural features of telomeres and through which mechanisms do they ensure chromosome end protection? What is the molecular basis of the telomeric cap and how does it act to sequester the chromosome end? Here I discuss data gathered in the last few years, suggesting that the protection of human chromosome ends primarily depends on the telomeric protein TRF2 and that telomere capping involves the formation of a higher order structure, the telomeric loop or t-loop.

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Section: Cellular Consequences Of Telomere Dysfunction: Apoptosis Andmentioning

confidence: 99%

Protection of mammalian telomeres

2002

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“…It has been shown that the telomeres of a normal somatic cell shorten with progressive cell divisions (Olovnikov, 1971;Harvey et al, 1990;Hastie et al, 1990;Lindsey et al, 1991;Allsopp et al, 1992;Allsopp and Harley, 1995). This appears to be due, at least in part, to passive loss caused by the`end replication problem' (Watson, 1972;Levy et al, 1992), and recent evidence suggests that there may also be active shortening of the C-rich telomeric strand (Makarov et al, 1997;McElligott and Wellinger, 1997). According to the telomere hypothesis of senescence the limited replicative potential of normal cells is due to the telomeres reaching critically short lengths after a number of cell divisions and consequently triggering senescence (Olovnikov, 1971), for review see Reddel (1998).…”

Section: Introductionmentioning

confidence: 99%

Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids

et al. 1999

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Some immortalized cell lines maintain their telomeres in the absence of detectable telomerase activity by an alternative (ALT) mechanism. To study how telomere maintenance is controlled in ALT cells, we have fused an ALT cell line GM847 (SV40 immortalized human skin ®broblasts) with normal ®broblasts or with telomerase positive immortal human cell lines and have examined their proliferative potential and telomere dynamics. The telomeres in ALT cells are characteristically very heterogeneous in length, ranging from very short to very long. The ALT6normal hybrids underwent a rapid reduction in telomeric DNA and entered a senescencelike state. Immortal segregants rapidly reverted to the ALT telomere phenotype. Fusion of ALT cells to telomerase-positive immortal cells in the same immortalization complementation group resulted in hybrids that appeared immortal and also exhibited repression of the ALT telomere phenotype. In these hybrids, which were all telomerase-positive, we observed an initial rapid loss of most long telomeres, followed either by gradual loss of the remaining long telomeres at a rate similar to the rate of telomere shortening in normal telomerase-negative cells, or by maintenance of shortened telomeres. These data indicate the existence of a mechanism of rapid telomere deletion in human cells. They also demonstrate that normal cells and at least some telomerase-positive immortal cells contain repressors of the ALT telomere phenotype.

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“…Telomeres are composed of double-stranded TTAGGG repeats (8 to 13 kbp long) followed by a 30-to 200-bp single-stranded 3= overhang (16)(17)(18)(19). Telomeres protect the chromosome against information loss and instability (20,21) and are shortened every time a cell divides.…”

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confidence: 99%

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

Gilbert-Girard

Gravel

Artusi

et al. 2017

J Virol

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Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes using a mechanism that remains poorly understood. To achieve a better understanding of the HHV-6A/B integration mechanism, we made use of BRACO-19, a compound that stabilizes G-quadruplex secondary structures and prevents telomere elongation by the telomerase complex. First, we analyzed the folding of telomeric sequences into G-quadruplex structures and their binding to BRACO-19 using G-quadruplex-specific antibodies and surface plasmon resonance. Circular dichroism studies indicate that BRACO-19 modifies the conformation and greatly stabilizes the G-quadruplexes formed in G-rich telomeric DNA. Subsequently we assessed the effects of BRACO-19 on the HHV-6A initial phase of infection. Our results indicate that BRACO-19 does not affect entry of HHV-6A DNA into cells. We next investigated if stabilization of G-quadruplexes by BRACO-19 affected HHV-6A's ability to integrate its genome into host chromosomes. Incubation of telomerase-expressing cells with BRACO-19, such as HeLa and MCF-7, caused a significant reduction in the HHV-6A integration frequency (P Ͻ 0.002); in contrast, BRACO-19 had no effect on HHV-6 integration frequency in U2OS cells that lack telomerase activity and elongate their telomeres through alternative lengthening mechanisms. Our data suggest that the fluidity of telomeres is important for efficient chromosomal integration of HHV-6A and that interference with telomerase activity negatively affects the generation of cellular clones containing integrated HHV-6A.IMPORTANCE HHV-6A/B can integrate their genomes into the telomeres of infected cells. Telomeres consist of repeated hexanucleotides (TTAGGG) of various lengths (up to several kilobases) and end with a single-stranded 3= extension. To avoid recognition and induce a DNA damage response, the single-stranded overhang folds back on itself and forms a telomeric loop (T-loop) or adopts a tertiary structure, referred to as a G-quadruplex. In the current study, we have examined the effects of a G-quadruplex binding and stabilizing agent, BRACO-19, on HHV-6A chromosomal integration. By stabilizing G-quadruplex structures, BRACO-19 affects the ability of the telomerase complex to elongate telomeres. Our results indicate that BRACO-19 reduces the number of clones harboring integrated HHV-6A. This study is the first of its kind and suggests that telomerase activity is essential to restore a functional telomere of adequate length following HHV-6A integration.

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The terminal DNA structure of mammalian chromosomes

Cited by 320 publications

References 56 publications

Protection of mammalian telomeres

Protection of mammalian telomeres

Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

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