Telomerase abrogates aneuploidy‐induced telomere replication stress, senescence and cell depletion

Meena, Jitendra K.; Cerutti, Aurora; Beichler, Christine; Morita, Yohei; Bruhn, Christopher; Kumar, Mukesh; Kraus, Johann M.; Speicher, Michael R.; Wang, Zhao‐Qi; Kestler, Hans A.; Fagagna, Fabrizio d’Adda di; Güneş, Çagatay; Rudolph, K. Lenhard

doi:10.15252/embj.201797470

Cited by 16 publications

(20 citation statements)

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“…It has been demonstrated that telomere shortening caused by downregulation of telomerase results in radiosensitization (18)(19)(20)(21)(22)(23)(37)(38)(39), and, conversely, that increased telomerase expression is linked to apoptosis resistance and enhanced DNA repair (7). Telomerase protects aneuploid cells against replication stress, and promotes genomic stability in cancer cells (40,41). Moreover, oxidative DNA damage, which is a major determinant of radiation toxicity, stimulates telomerase activity (42).…”

Section: Discussionmentioning

confidence: 99%

Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells

et al. 2019

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Telomerase is expressed in the majority (>85%) of tumors, but has restricted expression in normal tissues. Long-term telomerase inhibition in malignant cells results in progressive telomere shortening and reduction in cell proliferation. Here we report the synthesis and characterization of radiolabeled oligonucleotides that target the RNA subunit of telomerase, hTR, simultaneously inhibiting enzymatic activity and delivering radiation intracellularly. Oligonucleotides complementary (Match) and noncomplementary (Scramble or Mismatch) to hTR were conjugated to diethylenetriaminepentaacetic dianhydride (DTPA), allowing radiolabeling with the Auger electron-emitting radionuclide indium-111 (111 In). Match oligonucleotides inhibited telomerase activity with high potency, which was not observed with Scramble or Mismatch oligonucleotides. DTPA-conjugation and 111 In-labeling did not change telomerase inhibition. In telomerase-positive cancer cells, unlabeled Match oligonucleotides had no effect on survival, however, 111 In-labeled Match oligonucleotides significantly reduced clonogenic survival and upregulated the DNA damage marker gH2AX. Minimal radiotoxicity and DNA damage was observed in telomerase-negative cells exposed to 111 In-Match oligonucleotides. Match oligonucleotides localized in close proximity to nuclear Cajal bodies in telomerasepositive cells. In comparison with Match oligonucleotides, 111 In-Scramble or 111 In-Mismatch oligonucleotides demonstrated reduced retention and negligible impact on cell survival. This study indicates the therapeutic activity of radiolabeled oligonucleotides that specifically target hTR through potent telomerase inhibition and DNA damage induction in telomerase-expressing cancer cells and paves the way for the development of novel oligonucleotide radiotherapeutics targeting telomerase-positive cancers. Significance: These findings present a novel radiolabeled oligonucleotide for targeting telomerase-positive cancer cells that exhibits dual activity by simultaneously inhibiting telomerase and promoting radiation-induced genomic DNA damage.

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Section: Discussionmentioning

confidence: 99%

Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells

et al. 2019

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“…In addition to short telomere-triggered replicative senescence, a myriad of other stressors such as tumor suppressor loss, hyperactive oncogenic mutation (Serrano et al 1997), oxidative stress (von Zglinicki 2002), aneuploidy (Meena et al 2015), and genotoxic chemical exposure have also been shown to induce senescence, resulting in a variety of cellular alterations. These include strongly elevated secretion of cytokines and chemokines through the senescence-associated secretory phenotype (SASP) pathway (Coppe et al 2008;Acosta 2013), remodeling of the extracellular matrix (ECM) through secretion of metalloproteases and ECM components (Krizhanovsky 2008), alteration of gene expression networks , and a globally reshaped epigenetic landscape (Cruickshanks et al 2013).…”

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confidence: 99%

A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM–p53 signaling

Wang

Sack

et al. 2016

Genes Dev.

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Senescence stimuli activate multiple tumor suppressor pathways to initiate cycle arrest and a differentiation program characteristic of senescent cells. We performed a two-stage, gain-of-function screen to select for the genes whose enhanced expression can bypass replicative senescence. We uncovered multiple genes known to be involved in p53 and Rb regulation and ATM regulation, two components of the CST (CTC1-STN1-TEN1) complex involved in preventing telomere erosion, and genes such as REST and FOXO4 that have been implicated in aging. Among the new genes now implicated in senescence, we identified DLX2, a homeobox transcription factor that has been shown to be required for tumor growth and metastasis and is associated with poor cancer prognosis. Growth analysis showed that DLX2 expression led to increased cellular replicative life span. Our data suggest that DLX2 expression reduces the protein components of the TTI1/TTI2/TEL2 complex, a key complex required for the proper folding and stabilization of ATM and other members of the PIKK (phosphatidylinositol 3-kinase-related kinase) family kinase, leading to reduced ATM-p53 signaling and senescence bypass. We also found that the overexpression of DLX2 exhibited a mutually exclusive relationship with p53 alterations in cancer patients. Our functional screen identified novel players that may promote tumorigenesis by regulating the ATM-p53 pathway and senescence.

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“…18 Replication stress is one of the major sources of genomic instability in the early stages of tumorigenesis. [19][20][21] Several examples support this hypothesis: e.g.…”

Section: Aneuploidy Triggers Genomic Instability In Human Cellsmentioning

confidence: 99%

Too much to handle — how gaining chromosomes destabilizes the genome

Passerini

Storchová

2016

Cell Cycle

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Most eukaryotic organisms are diploid, with 2 chromosome sets in their nuclei. Whole chromosomal aneuploidy, a deviation from multiples of the haploid chromosome number, arises from chromosome segregation errors and often has detrimental consequences for cells. In humans, numerical aneuploidy severely impairs embryonic development and the rare survivors develop disorders characterized by multiple pathologies. Moreover, as many as 75 % of malignant tumors display aneuploidy. Although the exact contribution of aneuploidy to tumorigenesis remains unclear, previous studies have suggested that aneuploidy may affect the maintenance of genome integrity. We found that human cells with extra chromosomes showed phenotypes suggestive of replication defects, a phenomenon which we went on to characterize as being due to the aneuploidy-driven downregulation of replication factors, in particular of the replicative helicase MCM2-7. Thus, missegregation of even a single chromosome can further promote genomic instability and thereby contribute to tumor development. In this review we will examine the possible causes of downregulation of replicative factors and discuss the consequences of genomic instability in aneuploid cells.

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Telomerase abrogates aneuploidy‐induced telomere replication stress, senescence and cell depletion

Cited by 16 publications

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Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells

Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells

A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM–p53 signaling

Too much to handle — how gaining chromosomes destabilizes the genome

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