Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway

Chen, Yi‐An; Shen, Yi-Ling; Hsia, Hsuan-Yu; Tiang, Yee-Peng; Sung, Tzu-Ling; Chen, Liuh‐Yow

doi:10.1038/nsmb.3498

Cited by 123 publications

(120 citation statements)

References 46 publications

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“…Chen et al also showed that ATRX, Daxx, and H3.3 are required for ECTR‐induced IRF3 phosphorylation and IFN‐β expression in BJ fibroblasts. ATRX–Daxx–H3.3 deficiency in various human cancers and cell lines is highly associated with ALT activity .…”

Section: Sensing Of Free Telomeric Dna From Alt By Cgas–stingmentioning

confidence: 98%

Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches

2018

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The cyclic GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway mediates anti‐microbial innate immunity by inducing the production of type I interferons (IFNs) and inflammatory cytokines upon recognition of microbial DNA. Recent studies reveal that self‐DNA from tumors and by‐products of genomic instability also activates the cGAS–STING pathway and either promotes or inhibits tumor development. This has led to the development of cancer therapeutics using STING agonists alone and in combination with conventional cancer treatment or immune checkpoint targeting. On the other hand, for cancers lacking the cGAS–STING pathway and thus a regular innate immunity response, oncolytic virus therapy has been shown to have therapeutic potential. We here review and discuss the dichotomous roles of the cGAS–STING pathway in cancer development and therapeutic approaches.

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Section: Sensing Of Free Telomeric Dna From Alt By Cgas–stingmentioning

confidence: 98%

Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches

2018

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“…This pathway involves a cyclic GMP-AMP synthase (cGAS) sensor and triggers an interferon expression program, including interferon beta (IF), driving inflammation in vivo [118]. The cGAS-STING DNA sensing pathway acts as a protective mechanism by activating anti-tumor T cell responses [119]. ATRX loss alone may promote STING activation, causing antiproliferative effects and immune response promotion in vivo .…”

Section: Molecular Mechanisms Altered In Atrx-negative Gliomamentioning

confidence: 99%

“…ATRX loss alone may promote STING activation, causing antiproliferative effects and immune response promotion in vivo . For this reason, ATRX-null cells develop STING inactivation to allow for survival and ALT progression after ATRX loss [119]. These findings indicate that ATRX cancer cells may be vulnerable to STING activation.…”

Section: Molecular Mechanisms Altered In Atrx-negative Gliomamentioning

confidence: 99%

“…This requires targeting of the vulnerabilities of these cells. The possibility of exploiting the cGAS-STING DNA sensing pathway [119] provides opportunities of eliciting an immune response against ATRX-null ALT cells. Also, as was mentioned before, ATRX mutated cells have impaired senescence activation, but at the same time they express senescence promoting features that are a consequence of their genetic instability.…”

Section: Expert Opinionmentioning

confidence: 99%

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Mutant ATRX: uncovering a new therapeutic target for glioma

Haase

Garcia-Fabiani

Carney

et al. 2018

Expert Opinion on Therapeutic Targets

121

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Introduction ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives. Expert opinion ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g., DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

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“…As part of a cell-intrinsic replicative stress response, prostate cancer cells continuously shed genomic DNA into the cytosol due to cleavage of DNA at stalled replication forks by the DNA repair endonuclease MUS81, which results in activation of STING-dependent cytosolic DNA sensing and contributes to tumor immunogenicity and rejection [56]. Extra-chromosomal telomere repeat DNA (ECTR) fragments, generated by trimming of telomeres elongated through the pro-oncogenic alternative lengthening of telomeres (ATL) pathway, accumulate in ~10–15% of cancer cells and can also trigger cGAS–STING–IFN-I signaling [57]. Notably, in ALT cancer cells cytosolic DNA sensing is defective, suggesting that loss of cell-intrinsic self-DNA sensing is requirement for transformation and maintenance of ALT cells.…”

Section: Cancer Cancer Therapy and Genotoxic Stressmentioning

confidence: 99%

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

Dhanwani

Takahashi

Sharma

2018

Current Opinion in Immunology

100

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In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2′–5′-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS–STING–IRF3 response is triggered by direct recognition of the DNA genomes of bacteria and viruses, but also during RNA virus infection, neoplastic transformation, tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno-stimulatory DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived DNA substrates, including endogenous retroviral elements, mitochondrial DNA (mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults.

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Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway

Cited by 123 publications

References 46 publications

Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches

Role of the cGAS–STING pathway in cancer development and oncotherapeutic approaches

Mutant ATRX: uncovering a new therapeutic target for glioma

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

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