G-Quadruplexes at Telomeres: Friend or Foe?

Abstract

Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, such as four-stranded G-quadruplexes. This has long prompted speculation that G-quadruplexes play a positive role in telomere biology, resulting in selection for G-rich tandem telomere repeats during evolution. There is some evidence that G-quadruplexes at telomeres may play a protective capping role, at least in yeast, and that they may positively affect telomere maintenance by either the enzyme telomerase or by recombination-based mechanisms. On the other hand, G-quadruplex formation in telomeric DNA, as elsewhere in the genome, can form an impediment to DNA replication and a source of genome instability. This review summarizes recent evidence for the in vivo existence of G-quadruplexes at telomeres, with a focus on human telomeres, and highlights some of the many unanswered questions regarding the location, form, and functions of these structures.

G-Quadruplex Structures Colocalize with Transcription Factories and Nuclear Speckles Surrounded by Acetylated and Dimethylated Histones H3

“…Thus, an appearance of G4s (visualized by the antibody against G4s [clone 1H6]) is mostly of nontelomeric origin ( Figure 8 A). However, immunofluorescence-FISH with G-quadruplex antibody BG4 and telomere-specific DNA probe showed the important biological role of G4s in telomeres in the middle S-phase of the cell cycle [ 4 , 47 ]. Interestingly, in vivo dynamics of telomeric G-quadruplex structures was published by Bryan [ 47 ].…”

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

“…Accordingly, telomerase inhibition offers a reasonable targeted approach to hinder tumor growth. With the G/C-rich telomere sequences comprising some of the most well-studied G4 and i-motifs [78,79], the stabilization of these structures is an active area of drug development in the field. The first reports that stabilization of G4s with small molecules inhibited telomerase activity started in the late 1990s [58], while telomeric i-motif stabilization was not demonstrated until 2012.…”

Folding and Persistence Time of Intramolecular G-Quadruplexes Transiently Embedded in a DNA duplex

“…It is The copyright holder for this preprint this version posted January 4, 2021. ; https://doi.org/10.1101/2021.01.04.425278 doi: bioRxiv preprint sequence, they adopt different folding patterns and can form from the same (intramolecular) or distinct (intermolecular) nucleic acid strands (1)(2)(3). Potential G4-forming motifs are widespread across the genomes of a large spectrum of organisms from bacteria to mammals (4)(5)(6)(7)(8), and the formation of stable G4 structures in vivo has been linked to replication (9)(10)(11), oncogene expression (12)(13)(14), translation (15)(16)(17), DNA repair (18,19) telomere maintenance (20) or epigenetic marking of a DNA locus (21)(22)(23).…”

“…Depending on their sequence, they adopt different folding patterns and can form from the same (intramolecular) or distinct (intermolecular) nucleic acid strands (1–3). Potential G4-forming motifs are widespread across the genomes of a large spectrum of organisms from bacteria to mammals (4–8), and the formation of stable G4 structures in vivo has been linked to replication (9–11), oncogene expression (12–14), translation (15–17), DNA repair (18, 19) telomere maintenance (20) or epigenetic marking of a DNA locus (21–23). Questions around the physiological conditions for their formation and their biological roles have made G4 structures the focus of extensive in vitro and in vivo studies over the last two decades.…”