Abstract
G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation.
Highlights
Telomeres, specialized protein–DNA structures at the ends of chromosomes that contain runs of guanines, are thought to play an important role in genomic stability
Emodin is screened as a potential G4 ligand that could stabilize the formation of G4s in vitro
We observed that emodin exposure facilitated the formation of G4s in the telomeric region and induced telomere dysfunction, which led to cellular apoptosis and senescence
Summary
Telomeres, specialized protein–DNA structures at the ends of chromosomes that contain runs of guanines, are thought to play an important role in genomic stability. A more recent study indicated that telomerase assembly and recruitment are regulated by ATM and ATR, which are two key proteins that play essential roles in the DNA damage response[13]. Due to their G-rich and repetitive nature, telomeres can adopt secondary structures known as G4s14. The stabilization of G4s at telomeres impacts telomere association, recombination, and replication, leading to telomere dysfunction, observed as incomplete end-replication, abnormal telomere DNA breakage, loss of telomere capping or critical telomere shortening[15,16,17]. The stabilization of G4 at telomeres has been considered a promising strategy in the field of anticancer therapy to kill highly proliferating cells[23]
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