Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX

Hu, Yang; Shi, Guang; Zhang, Laichen; Li, Feng; Jiang, Yuanling; Jiang, Shuai; Ma, Wenbin; Zhao, Yong; Songyang, Zhou; Huang, Junjiu

doi:10.1038/srep32280

Cited by 67 publications

(71 citation statements)

References 51 publications

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“…In our study, RAP1 downregulation led to the appearance of TIFs in the context of ATRX loss, suggesting that the two cooperate under normal conditions to maintain telomere capping. Consistent with this finding, telomere dysfunction induced by downregulation of other shelterin components, such as TPP1, also induces ALT in the ATRX-deficient setting (45). The dysfunctional telomeres induced by mutant IDH1-driven RAP1 downregulation do not bind 53BP1 (not shown) and as such do not appear to exist in a "fully uncapped" state (46).…”

Section: Discussionsupporting

confidence: 58%

Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma

et al. 2018

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A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower grade astrocytomas and secondary glioblastoma, we examined a hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb-deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the nonhomologous DNA end joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate reexpression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX-deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres by allowing IDH1-mutant ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis. Studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis and suggesting new therapeutic options to treat low-grade gliomas. .

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Section: Discussionsupporting

confidence: 58%

Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma

et al. 2018

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“…Unfortunately, the primary shortcoming associated with this methodology reflects the inherent biology of abnormally lengthened telomeres, which requires malignant cells to undergo multiple rounds of cell division before telomere attrition results in replicative senescence. This delay allows cancer cells to develop other mechanisms such as ALT to elongate telomeres and overcome the effects of telomere shortening caused by telomerase inhibition (Hu et al, 2016; Queisser et al, 2013). Our data support an alternate strategy of using telomerase activity in cancer cells as a “Trojan horse” to selectively deliver toxic, non-native nucleotides to induce telomere dysfunction and more immediate cell death in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…The primary short-coming of telomerase inhibitors, however, is that even after destroying telomerase activity, the cancer cells must go through multiple rounds of DNA replication before telomere attrition results in replicative senescence. This delay can allow cancer cells to develop other mechanisms of survival, such as alternative lengthening of telomeres (ALT), to overcome the effects of telomere shortening caused by telomerase inhibition (Hu et al, 2016; Queisser et al, 2013). To address this problem, we devised an alternative strategy for selectively targeting telomerase-positive cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Zeng

Hernandez-Sanchez

et al. 2018

Cell Reports

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SUMMARY Telomerase, the end-replication enzyme, is reactivated in malignant cancers to drive cellular immortality. While this distinction makes telomerase an attractive target for anti-cancer therapies, most approaches for inhibiting its activity have been clinically ineffective. As opposed to inhibiting telomerase, we use its activity to selectively promote cytotoxicity in cancer cells. We show that several nucleotide analogs, including 5-fluoro-2′-deoxyuridine (5-FdU) triphosphate, are effectively incorporated by telomerase into a telomere DNA product. Administration of 5-FdU results in an increased number of telomere-induced foci, impedes binding of telomere proteins, activates the ATR-related DNA-damage response, and promotes cell death in a telomerase-dependent manner. Collectively, our data indicate that telomerase activity can be exploited as a putative anti-cancer strategy.

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“…Depletion of DAXX and ATRX in telomerase‐positive cancer cells leads to activation of the ALT mechanism of telomere maintenance, which is associated with formation of longer telomeres (49) and up‐regulation of the telomere repeat‐containing RNA TERRA (41, 42, 50, 51). The placenta is known to contain longer telomeres than most somatic cells and also shows some of the hallmarks of ALT‐based telomere maintenance, which is most likely limited to a subset of placental cells.…”

Section: Discussionmentioning

confidence: 99%

VariableDAXXgene methylation is a common feature of placental trophoblast differentiation, preeclampsia, and response to hypoxia

et al. 2017

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Placental functioning relies on the appropriate differentiation of progenitor villous cytotrophoblasts (CTBs) into extravillous cytotrophoblasts (EVCTs), including invasive EVCTs, and the multinucleated syncytiotrophoblast (ST) layer. This is accompanied by a general move away from a proliferative, immature phenotype. Genome-scale expression studies have provided valuable insight into genes that are associated with the shift to both an invasive EVCT and ST phenotype, whereas genome-scale DNA methylation analysis has shown that differentiation to ST involves widespread methylation shifts, which are counteracted by low oxygen. In the current study, we sought to identify DNA methylation variation that is associated with transition from CTB to ST and from a noninvasive to invasive EVCT phenotype after culture on Matrigel. Of the several hundred differentially methylated regions that were identified in each comparison, the majority showed a loss of methylation with differentiation. This included a large differentially methylated region (DMR) in the gene body of death domain-associated protein 6 ( ), which lost methylation during both CTB syncytialization to ST and EVCT differentiation to invasive EVCT. Comparison to publicly available methylation array data identified the same DMR as among the most consistently differentially methylated genes in placental samples from preeclampsia pregnancies. Of interest, culture of CTB or ST in low oxygen increases methylation in the same region, which correlates with delayed differentiation. Analysis of combined epigenomics signatures confirmed DMR as a likely regulatory element, and direct gene expression analysis identified a positive association between methylation at this site and expression levels. The widespread dynamic nature of methylation in association with trophoblast differentiation and placenta-associated pathologies is consistent with an important role for this gene in proper placental development and function.-Novakovic, B., Evain-Brion, D., Murthi, P., Fournier, T., Saffery, R. Variable DAXX gene methylation is a common feature of placental trophoblast differentiation, preeclampsia, and response to hypoxia.

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Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX

Cited by 67 publications

References 51 publications

Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma

Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma

Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

VariableDAXXgene methylation is a common feature of placental trophoblast differentiation, preeclampsia, and response to hypoxia

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