Oncotarget

Research Papers:

Telomere targeting with a novel G-quadruplex-interactive ligand BRACO-19 induces T-loop disassembly and telomerase displacement in human glioblastoma cells

Guangtong Zhou, Xinrui Liu, Yunqian Li, Songbai Xu, Chengyuan Ma, Xinmin Wu, Ye Cheng, Zhiyun Yu, Gang Zhao and Yong Chen _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:14925-14939. https://doi.org/10.18632/oncotarget.7483

Metrics: PDF 2453 views  |   HTML 3583 views  |   ?  


Abstract

Guangtong Zhou1, Xinrui Liu1, Yunqian Li1, Songbai Xu1, Chengyuan Ma1, Xinmin Wu1, Ye Cheng1, Zhiyun Yu1, Gang Zhao1, Yong Chen1

1Department of Neurosurgery, First Hospital of Jilin University, Changchun, China

Correspondence to:

Yong Chen, e-mail: [email protected]

Gang Zhao, e-mail: [email protected]

Keywords: telomere, G-quadruplex, telomerase, DNA damage, T-loop

Received: August 19, 2015    Accepted: January 29, 2016    Published: February 18, 2016

ABSTRACT

Interference with telomerase and telomere maintenance is emerging as an attractive target for anticancer therapies. Ligand-induced stabilization of G-quadruplex formation by the telomeric DNA 3′-overhang inhibits telomerase from catalyzing telomeric DNA synthesis and from capping telomeric ends, making these ligands good candidates for chemotherapeutic purposes. BRACO-19 is one of the most effective and specific ligand for telomeric G4. It is shown here that BRACO-19 suppresses proliferation and reduces telomerase activity in human glioblastoma cells, paralleled by the displacement of telomerase from nuclear to cytoplasm. Meanwhile, BRACO-19 triggers extensive DNA damage response at telomere, which may result from uncapping and disassembly of telomeric T-loop structure, characterized by the formation of anaphase bridge and telomere fusion, as well as the release of telomere-binding protein from telomere. The resulting dysfunctional telomere ultimately provokes p53 and p21-mediated cell cycle arrest, apoptosis and senescence. Notably, normal primary astrocytes do not respond to the treatment of BRACO-19, suggesting the agent’s good selectivity for cancer cells. These results reinforce the notion that G-quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs for various tumors including malignant gliomas.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 7483