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Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA
Alternative lengthening of telomere (ALT) tumors maintain telomeres by a telomerase-independent mechanism and are characterized by a nuclear structure called the ALT-associated PML body (APB). TRF2 is a component of a telomeric DNA/protein complex called shelterin. However, TRF2 function in ALT cell...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099206/ https://www.ncbi.nlm.nih.gov/pubmed/18056407 http://dx.doi.org/10.1083/jcb.200703020 |
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author | Stagno D'Alcontres, Martina Mendez-Bermudez, Aaron Foxon, Jennifer L. Royle, Nicola J. Salomoni, Paolo |
author_facet | Stagno D'Alcontres, Martina Mendez-Bermudez, Aaron Foxon, Jennifer L. Royle, Nicola J. Salomoni, Paolo |
author_sort | Stagno D'Alcontres, Martina |
collection | PubMed |
description | Alternative lengthening of telomere (ALT) tumors maintain telomeres by a telomerase-independent mechanism and are characterized by a nuclear structure called the ALT-associated PML body (APB). TRF2 is a component of a telomeric DNA/protein complex called shelterin. However, TRF2 function in ALT cells remains elusive. In telomerase-positive tumor cells, TRF2 inactivation results in telomere de-protection, activation of ATM, and consequent induction of p53-dependent apoptosis. We show that in ALT cells this sequence of events is different. First, TRF2 inactivation/silencing does not induce cell death in p53-proficient ALT cells, but rather triggers cellular senescence. Second, ATM is constitutively activated in ALT cells and colocalizes with TRF2 into APBs. However, it is only following TRF2 silencing that the ATM target p53 is activated. In this context, PML is indispensable for p53-dependent p21 induction. Finally, we find a substantial loss of telomeric DNA upon stable TRF2 knockdown in ALT cells. Overall, we provide insight into the functional consequences of shelterin alterations in ALT cells. |
format | Text |
id | pubmed-2099206 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-20992062008-06-03 Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA Stagno D'Alcontres, Martina Mendez-Bermudez, Aaron Foxon, Jennifer L. Royle, Nicola J. Salomoni, Paolo J Cell Biol Research Articles Alternative lengthening of telomere (ALT) tumors maintain telomeres by a telomerase-independent mechanism and are characterized by a nuclear structure called the ALT-associated PML body (APB). TRF2 is a component of a telomeric DNA/protein complex called shelterin. However, TRF2 function in ALT cells remains elusive. In telomerase-positive tumor cells, TRF2 inactivation results in telomere de-protection, activation of ATM, and consequent induction of p53-dependent apoptosis. We show that in ALT cells this sequence of events is different. First, TRF2 inactivation/silencing does not induce cell death in p53-proficient ALT cells, but rather triggers cellular senescence. Second, ATM is constitutively activated in ALT cells and colocalizes with TRF2 into APBs. However, it is only following TRF2 silencing that the ATM target p53 is activated. In this context, PML is indispensable for p53-dependent p21 induction. Finally, we find a substantial loss of telomeric DNA upon stable TRF2 knockdown in ALT cells. Overall, we provide insight into the functional consequences of shelterin alterations in ALT cells. The Rockefeller University Press 2007-12-03 /pmc/articles/PMC2099206/ /pubmed/18056407 http://dx.doi.org/10.1083/jcb.200703020 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Stagno D'Alcontres, Martina Mendez-Bermudez, Aaron Foxon, Jennifer L. Royle, Nicola J. Salomoni, Paolo Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA |
title | Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA |
title_full | Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA |
title_fullStr | Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA |
title_full_unstemmed | Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA |
title_short | Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA |
title_sort | lack of trf2 in alt cells causes pml-dependent p53 activation and loss of telomeric dna |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099206/ https://www.ncbi.nlm.nih.gov/pubmed/18056407 http://dx.doi.org/10.1083/jcb.200703020 |
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