Abstract
The activation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape replicative senescence and apoptosis. Alternative lengthening of telomeres (ALT) is found in a subset of malignant brain tumors with poor outcomes. Here, we describe a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert, linked to a widespread hypomethylation of the tert promoter and increase in Terra expression precedes ALT development. Surprisingly, expression of tert during juvenile brain tumor development led to reduced proliferation of tumor cells and prolonged survival. Most importantly, expression of tert reverted all ALT features and normalizes TERRA expression, promoted heterochromatin formation at telomeres, and attenuated telomeric DNA damage. These data suggest that the activity of telomerase goes beyond telomere maintenance and has profound consequences on genome stability.
Highlights
Telomeres are nucleoprotein structures assembled at the end of eukaryotic chromosomes protecting them from fusions, degradation, and erroneous recombination events
In order to investigate telomere length in zebrafish brain tumors we used 1–2 month old zebrafish with RAS-induced brain tumors (Mayrhofer et al, 2017), here called RAS, and performed terminal restriction fragment (TRF) analysis followed by Southern blot
Telomere lengths of RAS brain tumors varied between samples and highly resemble the variations in the length of telomeres detected in U2OS cells (Supplementary Figure 1A), which are known Alternative lengthening of telomeres (ALT) positive human cancer cells
Summary
Telomeres are nucleoprotein structures assembled at the end of eukaryotic chromosomes protecting them from fusions, degradation, and erroneous recombination events. A minority of cancers use ALT to maintain telomere length, a mechanism based on homologous recombination (Dilley and Greenberg, 2015). 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. APBs contain ALT-specific contents and proteins involved in DNA recombination/replication, and this content includes telomeric DNA, the telomere binding
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