Rol de los ARN no codificantes en la respuesta al estrés oxidativo en condiciones fisiológicas y en el cáncer
Long non-coding RNAs transcribed from telomeres, known as TERRA\n(telomeric repeat-containing RNA), are associated with telomere and genome\nstability. TERRA expression is elevated in human cancer tissues, however little is\nknown about their function. Oxidative stress damages biomolecules and activ...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2018
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_6304 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_6304.dir/6304.PDF |
| Aporte de: |
| Sumario: | Long non-coding RNAs transcribed from telomeres, known as TERRA\n(telomeric repeat-containing RNA), are associated with telomere and genome\nstability. TERRA expression is elevated in human cancer tissues, however little is\nknown about their function. Oxidative stress damages biomolecules and activates\nsignaling cascades involved in cell proliferation, apoptosis, and metastasis. Since\ntelomeres are prone to oxidative damage leading to their dysfunction, the objective\nof the present work is to characterize TERRA expression in oxidative stress, the\nmechanisms involved and its relevance in EMT. H2O2 induces TERRA expression in\nHEK-293T cells, and is prevented by antioxidant treatment. It was reported ROS are\nincreased in brown (BAT) but not in white adipose tissue of mice exposed to cold.\nImportantly, we found increased TERRAs only in BAT of mice exposed to cold. In\nHEK-293T cells exposed to H2O2, ChIP shows that chromatin landscape is modified\nfavoring telomere transcription. TERRAs interact with HP1?/?, both proteins found\nrecruited to subtelomeres. HP1? interacts with transcriptional machinery and\nnuclear pore complex proteins, suggesting they are involved in TERRA regulation.\nTERRA induction is lost 1-2h after removal of H2O2 from culture medium,\nsuggesting they have protective functions. This is supported by rapid increase of\nTERRA upon a second H2O2 challenge. PKA inhibitor H89 blocks the increase of\nTERRA induced by H2O2, suggesting that PKA controls TERRA induction.\nTreatment of cells with drugs that disturb cytoskeleton integrity or growing cells on\nsurfaces of different stiffness that generate differential cytoskeleton organization\nalso modifies TERRA levels. In fact, cytoskeleton rearrangements of EMTtransformed\nNMuMG cells associate with higher TERRAs and lack response to\nH2O2, mimicking what occurs in breast cancer cells that exhibit telomere dysfunction\nevidenced by confocal microscopy. In summary, we show that TERRAs are induced\nin response to oxidative stress and during EMT, being potentially novel early\nmarkers of cancer progression. |
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