Research Papers:

Acute telomere deprotection prevents ongoing BFB cycles and rampant instability in p16INK4a-deficient epithelial cells

Aina Bernal, Marc Moltó-Abad, Daniel Domínguez and Laura Tusell _

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Oncotarget. 2018; 9:27151-27170. https://doi.org/10.18632/oncotarget.25502

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Aina Bernal1, Marc Moltó-Abad1,2, Daniel Domínguez1 and Laura Tusell1

1Unitat de Biologia Cel·lular, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain

2Current address: Unitat de Malalties Minoritàries, Hospital Universitari de la Vall d’Hebron, 08035 Barcelona, Spain

Correspondence to:

Laura Tusell, email: [email protected]

Keywords: MCF-10A; breast epithelial cells; chromosome instability; telomere-dysfunction; TRF2ΔBΔM

Received: June 28, 2017    Accepted: May 13, 2018    Published: June 05, 2018


Telomere dysfunction drives chromosome instability through endless breakage-fusion-bridge (BFB) cycles that promote the formation of highly rearranged genomes. However, reactivation of telomerase or ALT-pathway is required for genome stabilisation and full malignant transformation. To allow the unrestricted proliferation of cells at risk of transformation, we have established a conditional system of telomere deprotection in p16INK4a-deficient MCF-10A cells with modified checkpoints. After sustained expression of a dominant negative form of the shelterin protein TRF2 (TRF2ΔBΔM), cells with telomere fusion did progress to anaphase but no signs of ongoing BFB cycles were observed, thus anticipating proliferation defects. Indeed, 96 h TRF2ΔBΔM expression resulted in noticeable growth proliferation defects in the absence of cell cycle disturbances. Further transient periods of 96 h telomere uncapping did not result in cell cycle disturbances either. And reduction of the telomere damage to short acute deprotection periods did not in any case engender cells with a reorganised karyotype. Strikingly, the growth arrest imposed in cells showing dysfunctional telomeres was not accompanied by an activation of the DNA damage response at cellular level, or by the presence of visible markers of senescence or apoptosis. We propose that the deprotection of many telomeres simultaneously, even for a short time, results in a local activation of the cellular stress response which consequently triggers gradual cell withdrawal from cell cycle, restraining the onset of genomic instability.

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