Inhibition of telomerase by G-quartet DMA structures

Abstract

The ends or telomeres of the linear chromosomes of eukaryotes are composed of tandem repeats of short DNA sequences, one strand being rich in guanine (G strand) and the complementary strand in cytosine. Telomere synthesis involves the addition of telomeric repeats to the G strand by telomere terminal transferase (telomerase). Telomeric G-strand DNAs from a variety of organisms adopt compact structures, the most stable of which is explained by the formation of G-quartets. Here we investigate the capacity of the different folded forms of telomeric DNA to serve as primers for the Oxytricha nova telomerase in vitro. Formation of the K(+)-stabilized G-quartet structure in a primer inhibits its use by telomerase. Furthermore, the octanucleotide T4G4, which does not fold, is a better primer than (T4G4)2, which can form a foldback structure. We conclude that telomerase does not require any folding of its DNA primer. Folding of telomeric DNA into G-quartet structures seems to influence the extent of telomere elongation in vitro and might therefore act as a negative regulator of elongation in vivo.

(3 + 1) Assembly of Three Human Telomeric Repeats into an Asymmetric Dimeric G-Quadruplex

“…19 It has been shown that formation of G-quadruplexes by the telomeric G-rich strand inhibits the activity of telomerase. 20 This inhibition is most likely due to the trapping the 3′-end guanines within the G-tetrad core. Use of small molecules for stabilizing telomeric G-quadruplex has been proposed as one of the anti-telomerase strategies for the development of anticancer drugs.…”

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

“…The 3' terminal region of the G-rich strand of human telomeres is single-stranded and may adopt a G-quadruplex conformation [19]. This structure has been shown to directly inhibit telom-erase elongation in vitro [20]. Telomeres protect chromosomal ends from fusion events and provide a means for complete replication of the chromosome.…”

“…The non-folded, single-stranded form of the primer is required for optimal telomerase activity and qua-druplex formation has been shown to directly inhibit telomerase elongation in vitro [20]. A growing number of small molecules have been discovered to inhibit telomerase activ ity by inducing and/or stabilizing G-quartet structure [45,46], including l0H-indolo [3,2-b] quinoline derivatives [47].…”

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

“…G-quadruplex structures have been implicated in the elongation of telomeric DNA by telomerase (Han and Hurley, 2000). The nonfolding single-stranded telomere overhang is required for an optimal telomerase reaction, and G-quadruplex formation has been shown to inhibit telomerase elongation in vitro (Zahler et al, 1991). Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase, and thus are very attractive targets for drug design (Mergny and Helene, 1998).…”