G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells

Hasegawa, Daiki; Okabe, Sachiko; Okamoto, K.; Nakano, ﻿Ichiro; Shin‐ya, Kazuo; Seimiya, Hiroyuki

doi:10.1016/j.bbrc.2016.01.176

Cited by 34 publications

(28 citation statements)

References 32 publications

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“…HeLa LT TERC KO cells are derived from HeLa LT cells, and both are telomerase negative and ALT negative (when the cells were analyzed, they were at population doubling 50 and the telomere length was above 20 kb) (13). We also tested for other potential replication stress factors at telomeres, such as G-quadruplexes and R-loop formation, which have also been regarded as triggers of replication problems at telomeres (32,33). We first determined if G-quadruplexes and R-loop formations occur in telomeres.…”

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confidence: 99%

Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes

Min

Wright

Shay

2017

Molecular and Cellular Biology

175

213

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Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells and their human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in Replication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers. The TIMELESS/TIPIN complex suppresses telomere clustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them. In summary, ALT cells exhibit more telomere replication defects that result in persistent DNA damage responses at telomeres, leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggered by DNA replication stress, a potential driver of genomic duplications in cancer.

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mentioning

confidence: 99%

Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes

Min

Wright

Shay

2017

Molecular and Cellular Biology

175

213

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“…An example is given by the replicative stress caused by physical impediment to polymerase enzymatic activity of G4-stabilized structures [11,16,17]. An example is given by the replicative stress caused by physical impediment to polymerase enzymatic activity of G4-stabilized structures [11,16,17].…”

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confidence: 99%

Naphthalene diimide‐derivatives G‐quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells

et al. 2018

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In the present paper, the biological effects of three different naphthalene diimides (NDIs) G-quadruplex (G4) ligands (H-NDI-Tyr, H-NDI-NMe2, and tetra-NDI-NMe2) were comparatively evaluated to those exerted by RHPS4, a well-characterized telomeric G4-ligand, in an in vitro model of glioblastoma. Data indicated that NDIs were very effective in blocking cell proliferation at nanomolar concentrations, although displaying a lower specificity for telomere targeting compared to RHPS4. In addition, differently from RHPS4, NDIs failed to enhance the effect of ionizing radiation, thus suggesting that additional targets other than telomeres could be involved in the strong NDI-mediated anti-proliferative effects. In order to test telomeric off-target action of NDIs, a panel of genes involved in tumor progression, DNA repair, telomere maintenance, and cell-cycle regulation were evaluated at transcriptional and translational level. Specifically, the compounds were able to cause a marked reduction of TERT and BCL2 amounts as well as to favor the accumulation of proteins involved in cell cycle control. A detailed cytofluorimetric analysis of cell cycle progression by means of bromodeoxyuridine (BrdU) incorporation and staining of phospho-histone H3 indicated that NDIs greatly reduce the progression through S-phase and lead to G1 accumulation of BrdU-positive cells. Taken together, these data indicated that, besides effects on telomeres and oncogenes such as Tert and Bcl2, nanomolar concentrations of NDIs determined a sustained block of cell proliferation by slowing down cell cycle progression during S-phase. In conclusion, our data indicate that NDIs G4-ligands are powerful antiproliferative agents, which act through mechanisms that ultimately lead to altered cell-cycle control.

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“…72,73 Telomestatin especially inhibits the growth of glioma stem cells by inducing replication stress and DNA damage. 74,75 Y2H2-6M(4)-oxazole telomestatin derivative inhibits the growth of glioma stem cells and glioblastoma cells in vivo. 76 Other G4 ligands, pyridostatin, quarfloxin/CX-3543 and CX-5461, cause synthetic lethality in BRCA1/2-deficient 77,78 and ATRX-deficient cancer cells.…”

Section: Telomestatin a Natural G4 Ligand From Streptomyces Anulatusmentioning

confidence: 99%

Crossroads of telomere biology and anticancer drug discovery

Seimiya

2020

Cancer Science

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The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5′‐TTAGGG‐3′ repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination‐based mechanism to maintain telomeres and exhibit immortality. As the most frequent non‐coding mutations in cancer, gain‐of‐function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere‐directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter‐driven oncolytic adenoviruses. Tankyrase poly(ADP‐ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt‐driven cancer. Meanwhile, telomeric nucleic acids form a higher‐order structure called a G‐quadruplex (G4). G4s are formed genome‐wide and their dynamics affect various events, including replication, transcription, and translation. G4‐stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.

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G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells

Cited by 34 publications

References 32 publications

Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes

Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes

Naphthalene diimide‐derivatives G‐quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells

Crossroads of telomere biology and anticancer drug discovery

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