scholarly journals How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1112
Author(s):  
Jesmin Akter ◽  
Takehiko Kamijo
Keyword(s):  
Pediatric Cancer ◽  
Genome Stability ◽  
Therapeutic Strategies ◽  
Adverse Outcomes ◽  
Telomere Maintenance ◽  
Mycn Amplification ◽  
Genetic Aberrations ◽  
Maintenance Mechanism ◽  
Alternative Lengthening

Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts for 15% of all pediatric-cancer deaths. Patients with HRNB frequently present with widely metastatic disease, with tumors harboring recurrent genetic aberrations (MYCN amplification, TERT rearrangements, and ATRX mutations), which are mutually exclusive and capable of promoting TMM. This review provides recent insights into our understanding of TMM in NB tumors, and highlights emerging therapeutic strategies as potential treatments for telomerase- and ALT-positive tumors.

scholarly journals ALT: A Multi-Faceted Phenomenon

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 133 ◽  
Author(s):  
Aurore Sommer ◽  
Nicola J. Royle
Keyword(s):  
Molecular Markers ◽  
Cancer Cells ◽  
Targeted Therapies ◽  
Sequence Variation ◽  
Telomere Maintenance ◽  
Hallmarks Of Cancer ◽  
Telomere Elongation ◽  
Maintenance Mechanism ◽  
Alternative Lengthening ◽  
Made In

One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.

scholarly journals Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation

2020 ◽  
Vol 147 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Monica Sofia Ventura Ferreira ◽  
Mia Dahl Sørensen ◽  
Stefan Pusch ◽  
Dagmar Beier ◽  
Anne-Sophie Bouillon ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Isocitrate Dehydrogenase 1 ◽  
Maintenance Mechanism ◽  
Alternative Lengthening

scholarly journals Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer Subtypes

2011 ◽  
Vol 179 (4) ◽  
pp. 1608-1615 ◽  
Author(s):  
Christopher M. Heaphy ◽  
Andrea P. Subhawong ◽  
Seung-Mo Hong ◽  
Michael G. Goggins ◽  
Elizabeth A. Montgomery ◽  
...  
Keyword(s):  
Human Cancer ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Cancer Subtypes ◽  
Maintenance Mechanism ◽  
Alternative Lengthening

scholarly journals Changes in the Expression of Pre-Replicative Complex Genes in hTERT and ALT Pediatric Brain Tumors

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1028 ◽  
Author(s):  
Aurora Irene Idilli ◽  
Francesca Pagani ◽  
Emanuela Kerschbamer ◽  
Francesco Berardinelli ◽  
Manuel Bernabé ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Cancer Cells ◽  
Pediatric Brain Tumors ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Maintenance Mechanism ◽  
Alternative Lengthening ◽  
Differential Gene ◽  
Pediatric Brain

Background: The up-regulation of a telomere maintenance mechanism (TMM) is a common feature of cancer cells and a hallmark of cancer. Routine methods for detecting TMMs in tumor samples are still missing, whereas telomerase targeting treatments are becoming available. In paediatric cancers, alternative lengthening of telomeres (ALT) is found in a subset of sarcomas and malignant brain tumors. ALT is a non-canonical mechanism of telomere maintenance developed by cancer cells with no-functional telomerase. Methods: To identify drivers and/or markers of ALT, we performed a differential gene expression analysis between two zebrafish models of juvenile brain tumors, that differ only for the telomere maintenance mechanism adopted by tumor cells: one is ALT while the other is telomerase-dependent. Results: Comparative analysis of gene expression identified five genes of the pre-replicative complex, ORC4, ORC6, MCM2, CDC45 and RPA3 as upregulated in ALT. We searched for a correlation between telomerase levels and expression of the pre-replicative complex genes in a cohort of paediatric brain cancers and identified a counter-correlation between telomerase expression and the genes of the pre-replicative complex. Moreover, the analysis of ALT markers in a group of 20 patients confirmed the association between ALT and increased RPA and decreased H3K9me3 localization at telomeres. Conclusions: Our study suggests that telomere maintenance mechanisms may act as a driver of telomeric DNA replication and chromatin status in brain cancers and identifies markers of ALT that could be exploited for precise prognostic and therapeutic purposes.

Structural and functional characterization of the RBBP4–ZNF827 interaction and its role in NuRD recruitment to telomeres

2018 ◽  
Vol 475 (16) ◽  
pp. 2667-2679 ◽  
Author(s):  
Sile F. Yang ◽  
Ai-ai Sun ◽  
Yunyu Shi ◽  
Fudong Li ◽  
Hilda A. Pickett
Keyword(s):  
Amino Acids ◽  
Electrostatic Interactions ◽  
Zinc Finger Protein ◽  
Functional Characterization ◽  
Vital Role ◽  
Telomere Maintenance ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
Alternative Lengthening

The nucleosome remodeling and histone deacetylase (NuRD) complex is an essential multi-subunit protein complex that regulates higher-order chromatin structure. Cancers that use the alternative lengthening of telomere (ALT) pathway of telomere maintenance recruit NuRD to their telomeres. This interaction is mediated by the N-terminal domain of the zinc-finger protein ZNF827. NuRD–ZNF827 plays a vital role in the ALT pathway by creating a molecular platform for recombination-mediated repair. Disruption of NuRD binding results in loss of ALT cell viability. Here, we present the crystal structure of the NuRD subunit RBBP4 bound to the N-terminal 14 amino acids of ZNF827. RBBP4 forms a negatively charged channel that binds to ZNF827 through a network of electrostatic interactions. We identify the precise amino acids in RBBP4 required for this interaction and demonstrate that disruption of these residues prevents RBBP4 binding to both ZNF827 and telomeres, but is insufficient to decrease ALT activity. These data provide insights into the structural and functional determinants of NuRD activity at ALT telomeres.

scholarly journals Guiding ATR and PARP inhibitor combinations with chemogenomic screens

2021 ◽  
Author(s):  
Michal Zimmermann ◽  
Cynthia Bernier ◽  
Beatrice Kaiser ◽  
Sara Fournier ◽  
Li Li ◽  
...  
Keyword(s):  
Parp Inhibitor ◽  
Genetic Alterations ◽  
Telomere Maintenance ◽  
Maintenance Mechanism ◽  
Combination Strategies ◽  
Alternative Lengthening ◽  
Genome Wide ◽  
A Genome ◽  
Rnase H2

Combinations of inhibitors of Ataxia Telangiectasia- and Rad3-related kinase (ATRi) and poly(ADP-ribose) polymerases (PARPi) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this we performed a genome-wide CRISPR/Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations or the Alternative Lengthening of Telomeres telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. Altogether, we present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.

scholarly journals Alternative Lengthening of Telomeres is not synonymous with mutations in ATRX/DAXX

2020 ◽  
Author(s):  
Alexandre de Nonneville ◽  
Roger R. Reddel
Keyword(s):  
Large Scale ◽  
Telomere Maintenance ◽  
Whole Genome Sequence ◽  
Structural Variations ◽  
Alternative Lengthening Of Telomeres ◽  
Maintenance Mechanism ◽  
Alternative Lengthening ◽  
Different Types ◽  
Promoter Mutations ◽  
Pan Cancer

AbstractThe PCAWG Consortium has recently released an unprecedented set of tumor whole genome sequence (WGS) data from 2,658 cancer patients across 38 different primary tumor sites1. WGS is able to document the quantity and distribution of telomeric repeats2. In one of the papers analyzing the PCAWG dataset, Sieverling et al.3 confirmed previous data4 indicating that tumors with truncating ATRX or DAXX alterations, referred to as ATRX/DAXXtrunc, have an aberrant telomere variant repeat (TVR) distribution. By regarding these mutations, vs. TERT modifications (TERTmod; i.e. promoter mutations +/− amplifications +/− structural variations), as indicators of Alternative Lengthening of Telomeres (ALT) vs. telomerase, they built a random forest classifier for ALT-probability, and then associated genomic characteristics with the putative Telomere Maintenance Mechanism (TMM)3. However, we show here that equating ATRX/DAXXtrunc and TERTmod with ALT and telomerase, respectively, results in TMM predictions which correlate poorly with TMM assay data. ATRX/DAXXtrunc mutations are heterogeneously distributed in ALT-positive (ALT+) tumors of different types, as are TERTmod in telomerase-positive tumors4. Although these mutations are strongly associated with TMM, most tumors do not harbor them, making them an inadequate basis for building a classifier in a large-scale pan-cancer study4–7. Here, we provide a new analysis of the PCAWG data, based on C-circle assay (CCA)8 that is available for a subset of these tumors4,9,10. We show that the Sieverling et al. score overestimates the proportion of ALT associated with ATRX/DAXXtrunc and misclassifies ALT tumors when these mutations are absent. We also show some TVR correlate with ATRX/DAXXtrunc mutations, regardless of TMM. Finally, we propose a new classifier to identify ALT tumors in the PCAWG cohort.

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