Telomeric G-quadruplexes are a substrate and site of localization for human telomerase

Moye, Aaron L.; Porter, Karina C.; Cohen, Scott B.; Phan, Tram; Zyner, Katherine G.; Sasaki, Natsuki; Lovrecz, George O.; Beck, Jennifer L.; Bryan, Tracy M.

doi:10.1038/ncomms8643

Cited by 228 publications

(217 citation statements)

References 57 publications

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“…(2015) characterized the stable human telomeric G-quadruplexes and demonstrated that these G4s are able to extend into parallel, intermolecular conformations, aligning with the intrinsic RNA moiety of the human telomerase RNA (hTR). They also showed that telomerase colocalizes with a subset of telomeric G4 structures in vivo 27 . Additionally, structural and computational analysis revealed that pG4 sequences are found in ∼40% of gene promoter regions, mostly acting as transcriptional repressors 23,28,29 .…”

Section: Dna G-quadruplexesmentioning

confidence: 97%

RNA G-quadruplexes and their potential regulatory roles in translation

et al. 2016

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DNA guanine (G)-rich 4-stranded helical nucleic acid structures called G-quadruplexes (G4), have been extensively studied during the last decades. However, emerging evidence reveals that 5′- and 3′-untranslated regions (5′- and 3′-UTRs) as well as open reading frames (ORFs) contain putative RNA G-quadruplexes. These stable secondary structures play key roles in telomere homeostasis and RNA metabolism including pre-mRNA splicing, polyadenylation, mRNA targeting and translation. Interestingly, multiple RNA binding proteins such as nucleolin, FMRP, DHX36, and Aven were identified to bind RNA G-quadruplexes. Moreover, accumulating reports suggest that RNA G-quadruplexes regulate translation in cap-dependent and -independent manner. Herein, we discuss potential roles of RNA G-quadruplexes and associated trans-acting factors in the regulation of mRNA translation.

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Section: Dna G-quadruplexesmentioning

confidence: 97%

RNA G-quadruplexes and their potential regulatory roles in translation

et al. 2016

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“…Importantly, these different G-quadruplex structures can also display functional diversity with respect to ligand binding and specificity 10; 11 . In addition to a wealth of data characterizing G-quadruplex structure, stability, and specificity in vitro (see 12 ), the existence of G-quadruplexes has been confirmed in the telomeres of human cells, within the macronuclei of ciliates, and in Xenopus laevis egg extract 13; 14; 15; 16; 17 . However, the mechanisms which proteins and enzymes associate with telomere DNA and the ways they alter its ability to form stable alternative structures are not well understood.…”

Section: Introductionmentioning

confidence: 96%

POT1–TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism

Mullins

Rajavel

Hernandez-Sanchez

et al. 2016

Journal of Molecular Biology

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Telomeres are nucleoprotein complexes that reside at the ends of linear chromosomes and help maintain genomic integrity. POT1 and TPP1 are telomere-specific proteins that bind as a heterodimer to single-stranded telomere DNA to prevent illicit DNA damage responses and to enhance telomerase-mediated telomere extension. Telomere DNA is guanosine-rich and, as such, can form highly stable secondary structures including G-quadruplexes. G-quadruplex DNA folds into different topologies that are determined by several factors including monovalent ion composition and the precise sequence and length of the DNA. Here, we explore the influence of DNA secondary structure on POT1-TPP1 binding. Equilibrium binding assays reveal that the POT1-TPP1 complex binds G-quadruplex structures formed in buffers containing Na+ with an affinity that is 5-fold higher than for G-quadruplex structures formed in the presence of K+. However, binding of a second heterodimer is insensitive to DNA secondary structure, presumably due to unfolding resulting from binding of the first POT1-TPP1. We further show that the rate constant for POT1-TPP1-induced unfolding of DNA secondary structure is substantially faster for G-quadruplex topologies formed in the presence of Na+ ions. When bound to DNA, POT1-TPP1 forms complexes with similar CD spectra and enhances telomerase activity for all DNA substrates tested, regardless of substrate secondary structure or solution monovalent ion composition. Together, these data indicate that binding of POT1-TPP1 unfolds telomere secondary structure to assist loading of additional heterodimers and to ensure efficient promotion of telomerase-mediated extension.

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“…[14,15] Ar ange of small molecules has been shown to stronglyb ind and stabilise such G-quadruplexs tructures, thereby rendering these compounds potentiala nticancer drugs. [10,[16][17][18][19][20][21][22][23][24][25][26] Recent findings, such as the fact that parallel quadruplexes can still act as asubstrate for telomerase, [27] suggest,h owever,t hat indirect telomerase inhibition is not necessarilyt he dominant contribution in anticancer activity of quadruplex-bindingl igands.…”

Section: Introductionmentioning

confidence: 99%

A Water‐Soluble Tetraazaperopyrene Dye as Strong G‐Quadruplex DNA Binder

Hahn

Buurma

Gade

2016

Chemistry A European J

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The interactions of the water‐soluble tetraazaperopyrene dye 1 with ct‐DNA, duplex‐[(dAdT)12 ⋅(dAdT)12], duplex‐[(dGdC)12 ⋅(dGdC)12] as well as with two G‐quadruplex‐forming sequences, namely the human telomeric 22AG and the promotor sequence c‐myc, were investigated by means of UV/visible and fluorescence spectroscopy, isothermal titration calorimetry (ITC) and molecular docking studies. Dye 1 exhibits a high affinity for G‐quadruplex structures over duplex DNA structures. Furthermore, the ligand shows promising G‐quadruplex discrimination, with an affinity towards c‐myc of 2×107 m −1 (i.e., K d=50 nm), which is higher than for 22AG (4×106 m −1). The ITC data reveal that compound 1 interacts with c‐myc in a stoichiometric ratio of 1:1 but also indicate the presence of two identical lower affinity secondary binding sites per quadruplex. In 22AG, there are two high affinity binding sites per quadruplex, that is, one on each side, with a further four weaker binding sites. For both quadruplex structures, the high affinity interactions between compound 1 and the quadruplex‐forming nucleic acid structures are weakly endothermic. Molecular docking studies suggest an end‐stacking binding mode for compound 1 interacting with quadruplex structures, and a higher affinity for the parallel conformation of c‐myc than for the mixed‐hybrid conformation of 22AG. In addition, docking studies also suggest that the reduced affinity for duplex DNA structures is due to the non‐viability of an intercalative binding mode.

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Telomeric G-quadruplexes are a substrate and site of localization for human telomerase

Cited by 228 publications

References 57 publications

RNA G-quadruplexes and their potential regulatory roles in translation

RNA G-quadruplexes and their potential regulatory roles in translation

POT1–TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism

A Water‐Soluble Tetraazaperopyrene Dye as Strong G‐Quadruplex DNA Binder

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