Acute telomere deprotection prevents ongoing BFB cycles and rampant instability in p16 INK4a -deficient epithelial cells
Bernal Martínez, Aina (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Moltó Abad, Marc (Hospital Universitari Vall d'Hebron)
Domínguez, Daniel (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Tusell Padrós, Laura (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)

Data:	2018
Resum:	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 p16 INK4a -deficient MCF-10A cells with modified checkpoints. After sustained expression of a dominant negative form of the shelterin protein TRF2 (TRF2 ΔBΔM), cells with telomere fusion did progress to anaphase but no signs of ongoing BFB cycles were observed, thus anticipating proliferation defects. Indeed, 96 h TRF2 ΔBΔM 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.
Ajuts:	Ministerio de Economía y Competitividad SAF2013-43801-P Agència de Gestió d'Ajuts Universitaris i de Recerca 2014-SGR-524
Nota:	Altres ajuts: AB and DD were supported by a Universitat Autònoma de Barcelona fellowship (456-01-1/2012) and Generalitat de Catalunya fellowship (2013FI_B200188).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	MCF-10A ; Breast epithelial cells ; Chromosome instability ; Telomere-dysfunction ; TRF2 ΔBΔM
Publicat a:	Oncotarget, Vol. 9 (june 2018) , p. 27151-27170, ISSN 1949-2553

DOI: 10.18632/oncotarget.25502
PMID: 29930757

20 p, 8.2 MB

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