G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma

Wang, Yuxiang; Yang, Jie; Wild, Aaron T.; Wu, Wei; Shah, Rachna; Danussi, Carla; Riggins, Gregory J.; Kannan, Kasthuri; Sulman, Erik P.; Chan, Timothy A.; Huse, Jason T.

doi:10.1038/s41467-019-08905-8

Cited by 150 publications

(125 citation statements)

References 70 publications

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“…Loss of ATRX was shown to sensitize cells to DNA-damaging agents [101]. ATRX deficiency was also shown to promote accumulation of G-quadruplexes, making cells sensitive to a G4-stabilizing compound [102]. Furthermore, a mutant herpes simplex virus type 1 (HSV-1) infects ATRX-deficient cells much more efficiently than ATRX-proficient cells, selectively killing ATRX-deficient cells [103].…”

Section: Therapeutic Outlooksmentioning

confidence: 99%

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

2020

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To escape replicative senescence, cancer cells have to overcome telomere attrition during DNA replication. Most of cancers rely on telomerase to extend and maintain telomeres, but 4-11% of cancers use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). ALT is prevalent in cancers from the mesenchymal origin and usually associates with poor clinical outcome. Given its critical role in protecting telomeres and genomic integrity in tumor cells, ALT is an Achilles heel of tumors and an attractive target for cancer therapy. Here, we review the recent progress in the mechanistic studies of ALT, and discuss the emerging therapeutic strategies to target ALT-positive cancers.

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Section: Therapeutic Outlooksmentioning

confidence: 99%

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

2020

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“…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. 79 CM03, another G4 ligand, inhibits the growth of pancreatic xenograft tumors. 80 This ligand represses the genes that have putative G4-forming sequences and are frequently upregulated in pancreatic cancer.…”

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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“…Previous work has suggested that ATRX binds to these G4 structures (81), and has a potential role in their resolution, with ATRX-null cells displaying higher numbers of G4 structures (81,82). Consistent with this notion, recent work has shown that in an ATRX-null background cells are unable to effectively tolerate the induction of these structures through chemical stabilization, raising the possibility for their use in either selectively killing ATRX-null ALT cells, or in presensitizing these cells to other therapeutic agents such as ionizing radiation (82,83). A number of G4 stabilizers are currently in clinical trials, with one example being CX-3543 (Quarfloxin) (84).…”

Section: Dna Secondary Structures and R-loops In Altmentioning

confidence: 99%

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

et al. 2020

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Achieving replicative immortality is a crucial step in tumorigenesis and requires both bypassing cell cycle checkpoints and the extension of telomeres, sequences that protect the distal ends of chromosomes during replication. In the majority of cancers this is achieved through the enzyme telomerase, however a subset of cancers instead utilize a telomerase-independent mechanism of telomere elongation-the Alternative Lengthening of Telomeres (ALT) pathway. Recent work has aimed to decipher the exact mechanism that underlies this pathway. To this end, this pathway has now been shown to extend telomeres through exploitation of DNA repair machinery in a unique process that may present a number of druggable targets. The identification of such targets, and the subsequent development or repurposing of therapies to these targets may be crucial to improving the prognosis for many ALT-positive cancers, wherein mean survival is lower than non-ALT counterparts and the cancers themselves are particularly unresponsive to standard of care therapies. In this review we summarize the recent identification of many aspects of the ALT pathway, and the therapies that may be employed to exploit these new targets.

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G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma

Cited by 150 publications

References 70 publications

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

Crossroads of telomere biology and anticancer drug discovery

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

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