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Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA.
J Cell Biol. 2007 Dec 03; 179(5):855-67.JC

Abstract

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.

Authors+Show Affiliations

MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, England, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18056407

Citation

Stagno D'Alcontres, Martina, et al. "Lack of TRF2 in ALT Cells Causes PML-dependent P53 Activation and Loss of Telomeric DNA." The Journal of Cell Biology, vol. 179, no. 5, 2007, pp. 855-67.
Stagno D'Alcontres M, Mendez-Bermudez A, Foxon JL, et al. Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA. J Cell Biol. 2007;179(5):855-67.
Stagno D'Alcontres, M., Mendez-Bermudez, A., Foxon, J. L., Royle, N. J., & Salomoni, P. (2007). Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA. The Journal of Cell Biology, 179(5), 855-67.
Stagno D'Alcontres M, et al. Lack of TRF2 in ALT Cells Causes PML-dependent P53 Activation and Loss of Telomeric DNA. J Cell Biol. 2007 Dec 3;179(5):855-67. PubMed PMID: 18056407.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA. AU - Stagno D'Alcontres,Martina, AU - Mendez-Bermudez,Aaron, AU - Foxon,Jennifer L, AU - Royle,Nicola J, AU - Salomoni,Paolo, PY - 2007/12/7/pubmed PY - 2007/12/28/medline PY - 2007/12/7/entrez SP - 855 EP - 67 JF - The Journal of cell biology JO - J. Cell Biol. VL - 179 IS - 5 N2 - 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. SN - 1540-8140 UR - https://www.unboundmedicine.com/medline/citation/18056407/Lack_of_TRF2_in_ALT_cells_causes_PML_dependent_p53_activation_and_loss_of_telomeric_DNA_ L2 - https://rupress.org/jcb/article-lookup/doi/10.1083/jcb.200703020 DB - PRIME DP - Unbound Medicine ER -