Both the molecular details of ALT activation ( Cesare and Reddel, 2010) and the specificity for certain tumors, either with mesenchymal (sarcoma) or neuroectodermal (glioblastoma) origin ( Heaphy et al., 2011 Mangerel et al., 2014 Louis et al., 2016) remain to be defined. However, a minority of cancers use ALT to maintain telomere length, a mechanism based on homologous recombination ( Dilley and Greenberg, 2015). Most cancers reactivate telomerase, which is usually expressed at very low levels in somatic cells ( Kim et al., 1994). In order to attain unlimited proliferative capacity, cancer cells must adopt a telomere maintenance mechanism (TMM). Critically short telomeres trigger a DNA damage response, ultimately leading to an irreversible cell cycle arrest, known as senescence ( Harley et al., 1990). Telomeres are nucleoprotein structures assembled at the end of eukaryotic chromosomes protecting them from fusions, degradation, and erroneous recombination events. These data suggest that the activity of telomerase goes beyond telomere maintenance and has profound consequences on genome stability. Most importantly, expression of tert reverted all ALT features and normalizes TERRA expression, promoted heterochromatin formation at telomeres, and attenuated telomeric DNA damage. Surprisingly, expression of tert during juvenile brain tumor development led to reduced proliferation of tumor cells and prolonged survival. We discovered that reduced expression of tert, linked to a widespread hypomethylation of the tert promoter and increase in Terra expression precedes ALT development. Here, we describe a model of juvenile zebrafish brain tumor that progressively develops ALT. Alternative lengthening of telomeres (ALT) is found in a subset of malignant brain tumors with poor outcomes.
The activation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape replicative senescence and apoptosis.
4Telomerase, Cancer and Aging, Department of Surgery, Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain.3Department of Science, Roma Tre University, Rome, Italy.2Pathology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.1Department of Cellular, Computational and Integrative Biology – CIBIO, University of Trento, Trento, Italy.
Aurora Irene Idilli 1, Emilio Cusanelli 1, Francesca Pagani 2, Francesco Berardinelli 3, Manuel Bernabé 4, María Luisa Cayuela 4, Pietro Luigi Poliani 2 and Maria Caterina Mione 1*
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