Consecutive Formation of G‐Quadruplexes in Human Telomeric‐Overhang DNA: A Protective Capping Structure for Telomere Ends

Xu, Yan; Ishizuka, Takumi; Kurabayashi, Kaori; Komiyama, Makoto

doi:10.1002/anie.200903858

Cited by 126 publications

(94 citation statements)

References 39 publications

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“…The same conclusion was published in the next year (2006) by Sugimoto's group [67]. The beads-on-a-string-like arrangement of the long telomere DNAs was experimentally verified by atomic force microscopy in 2009 [68]. The atomic force microscopy image of the beads is included with the permission of the authors as an insert in Fig.…”

Section: Quadruplexes Of Long Human Telomeric Dnasupporting

confidence: 65%

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Circular dichroism and guanine quadruplexes

Vorlı́čková

Kejnovská

Sági³

et al. 2012

Methods

372

298

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Section: Quadruplexes Of Long Human Telomeric Dnasupporting

confidence: 65%

“…The arrangement of the long human telomere DNA molecules has been studied by numerous groups [67,68,[83][84][85][86][87][88]. Some studies did not observe interactions of the beads [67].…”

Section: Formation Of Higher-order Quadruplex Structuresmentioning

confidence: 99%

Circular dichroism and guanine quadruplexes

Vorlı́čková

Kejnovská

Sági³

et al. 2012

Methods

372

298

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“…Previous AFM studies of G4 DNA used either short telomeric sequence (four repeats), 3Ј tails of unknown lengths, or did not provide quantitative or distribution analysis of the images (31)(32)(33). Consequently, detailed information regarding the distribution and types of conformations of physiological telomeric tails was lacking.…”

Section: Physiological Telomere Tails Rarely Form the Maximummentioning

confidence: 99%

Single Molecule Studies of Physiologically Relevant Telomeric Tails Reveal POT1 Mechanism for Promoting G-quadruplex Unfolding

Wang

Nora

Ghodke

et al. 2011

Journal of Biological Chemistry

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Human telomeres are composed of duplex TTAGGG repeats and a 3 single-stranded DNA tail. The telomeric DNA is protected and regulated by the shelterin proteins, including the protection of telomeres 1 (POT1) protein that binds telomeric single-stranded DNA. The single-stranded tail can fold into G-quadruplex (G4) DNA. Both POT1 and G4 DNA play important roles in regulating telomere length homeostasis. To date, most studies have focused on individual quadruplexes formed by four TTAGGG repeats. Telomeric tails in human cells have on average six times as many repeats, and no structural studies have examined POT1 binding in competition with G4 DNA folding. Using single molecule atomic force microscopy imaging, we observed that the majority of the telomeric tails of 16 repeats formed two quadruplexes even though four were possible. The result that physiological telomeric tails rarely form the maximum potential number of G4 units provides a structural basis for the coexistence of G4 and POT1 on the same DNA molecule, which is observed directly in the captured atomic force microscopy images. We further observed that POT1 is significantly more effective in disrupting quadruplex DNA on long telomeric tails than an antisense oligonucleotide, indicating a novel POT1 activity beyond simply preventing quadruplex folding.Cells with linear chromosomes must solve the following two problems: the progressive lagging strand shortening with each cycle of DNA replication and the need to protect the ends of linear chromosomes from unwanted DNA damage responses (1). As a solution to both these problems, telomeres stand at the junction between aging, genomic stability, and cancer.Telomeres are composed of the "shelterin complex" of proteins and TTAGGG repeats of duplex DNA along with an ssDNA overhang or "tail" of 50 -500 nucleotides (1). The ssDNA tail can fold into G-quadruplex DNA (G4 DNA), 4 which consists of three tetrads of four guanines that form Hoogsteen base pairs with each other (Fig. 1A). These tetrads are in a square planar conformation and are stacked atop one another with the TTA sequences forming linker loops (2, 3). The formation of G4 DNA has been shown to inhibit the telomere-lengthening enzyme complex telomerase in vitro (4), although a recent in vivo study of Saccharomyces cerevisiae telomerase found that G4 DNA can promote the activity of yeast telomerase (5).Protection of telomeres 1 (POT1) is part of the shelterin protein complex and binds to single-stranded telomeric TTAGGG repeats (6, 7). POT1 protects mammalian chromosome ends from the ataxia telangiectasia mutated and Rad3-related (ATR)-dependent DNA damage response, inhibits 5Ј end resection at telomere termini, and regulates telomerase-mediated telomere extension (8). Although POT1 was shown to trap an oligonucleotide with four telomere repeats in an unfolded state to prevent G4 formation (4), the biological significance of this result is unclear. First, POT1 could not bind the short four telomere repeat substrate when the oligonucleotide was prefolded into...

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“…Formation of a higher-order architecture consistent with contiguous G4s was then revealed by atomic force microscopy [29]. A later in vitro study brought additional evidence of folding into two and three contiguous G4s [30].…”

Section: Introductionmentioning

confidence: 97%

Understanding the stability of DNA G-quadruplex units in long human telomeric strands

Bugaut

Alberti

2015

Biochimie

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Human telomeric DNA is composed of GGGTTA repeats. The presence of consecutive guanines makes the telomeric G-strand prone to fold into contiguous (or tandem) G-quadruplexes (G4s). The aim of this study was to provide a clarified picture of the stability of telomeric tandem G4 structures as a function of the number of G4 units and of boundary sequences, and an understanding of the diversity of their melting behaviors in terms of the single G4 units composing them. To this purpose we undertook an UV-spectroscopic investigation of the structure and stability of telomeric repeats potentially able to fold into up to four contiguous G4s, flanked or not by TTA sequences at their 5' and 3' extremities. We explain why the stability of (GGGTTA)4m-1GGG structures (m = 2, 3, 4 …) decreases with increasing the number m of G4 units, whereas the stability of TTA-(GGGTTA)4m-1GGG-TTA structures does not. Our results support that the inner G4 units have similar stabilities, whereas the stabilities of the terminal G4 units are modulated by their flanking nucleotides: in a TTA-(GGGTTA)4m-1GGG-TTA tandem context, the terminal G4 units are roughly as stable as the inner G4 units; while in a (GGGTTA)4m-1GGG tandem context, the G4 at the 5' extremity is more stable than the G4 at the 3' extremity, which in turn is more stable than an inner G4. Our study provides new information about the global and local stability of telomeric tandem G4 structures under near physiological conditions.

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Consecutive Formation of G‐Quadruplexes in Human Telomeric‐Overhang DNA: A Protective Capping Structure for Telomere Ends

Cited by 126 publications

References 39 publications

Circular dichroism and guanine quadruplexes

Circular dichroism and guanine quadruplexes

Single Molecule Studies of Physiologically Relevant Telomeric Tails Reveal POT1 Mechanism for Promoting G-quadruplex Unfolding

Understanding the stability of DNA G-quadruplex units in long human telomeric strands

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