Telomere targeting with a novel G-quadruplex-interactive ligand BRACO-19 induces T-loop disassembly and telomerase displacement in human glioblastoma cells
2016; Impact Journals LLC; Volume: 7; Issue: 12 Linguagem: Inglês
10.18632/oncotarget.7483
ISSN1949-2553
AutoresGuangtong Zhou, Xinrui Liu, Yunqian Li, Songbai Xu, Chengyuan Ma, Xinmin Wu, Ye Cheng, Zhiyun Yu, Gang Zhao, Yong Chen,
Tópico(s)DNA and Nucleic Acid Chemistry
Resumo// Guangtong Zhou 1 , Xinrui Liu 1 , Yunqian Li 1 , Songbai Xu 1 , Chengyuan Ma 1 , Xinmin Wu 1 , Ye Cheng 1 , Zhiyun Yu 1 , Gang Zhao 1 , Yong Chen 1 1 Department of Neurosurgery, First Hospital of Jilin University, Changchun, China Correspondence to: Yong Chen, e-mail: cy_9201982@aliyun.com Gang Zhao, e-mail: zhao_gangjlu@aliyun.com 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.
Referência(s)