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Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function
BACKGROUND: Secondary cultures of human fibroblasts display a finite lifespan ending at senescence. Loss of p53 function by mutation or viral oncogene expression bypasses senescence, allowing cell division to continue for an additional 10 – 20 doublings. During this time chromosomal aberrations seen...
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2005
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1262734/ https://www.ncbi.nlm.nih.gov/pubmed/16209708 http://dx.doi.org/10.1186/1477-3163-4-18 |
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author | Simpson, Dennis A Livanos, Elizabeth Heffernan, Timothy P Kaufmann, William K |
author_facet | Simpson, Dennis A Livanos, Elizabeth Heffernan, Timothy P Kaufmann, William K |
author_sort | Simpson, Dennis A |
collection | PubMed |
description | BACKGROUND: Secondary cultures of human fibroblasts display a finite lifespan ending at senescence. Loss of p53 function by mutation or viral oncogene expression bypasses senescence, allowing cell division to continue for an additional 10 – 20 doublings. During this time chromosomal aberrations seen in mitotic cells increase while DNA damage and decatenation checkpoint functions in G(2 )cells decrease. METHODS: To explore this complex interplay between chromosomal instability and checkpoint dysfunction, human fibroblast lines were derived that expressed HPV16E6 oncoprotein or dominant-negative alleles of p53 (A143V and H179Q) with or without the catalytic subunit of telomerase. RESULTS: Cells with normal p53 function displayed 86 – 93% G(1 )arrest after exposure to 1.5 Gy ionizing radiation (IR). Expression of HPV16E6 or p53-H179Q severely attenuated G(1 )checkpoint function (3 – 20% arrest) while p53-A143V expression induced intermediate attenuation (55 – 57% arrest) irrespective of telomerase expression. All cell lines, regardless of telomerase expression or p53 status, exhibited a normal DNA damage G(2 )checkpoint response following exposure to 1.5 Gy IR prior to the senescence checkpoint. As telomerase-negative cells bypassed senescence, the frequencies of chromosomal aberrations increased generally congruent with attenuation of G(2 )checkpoint function. Telomerase expression allowed cells with defective p53 function to grow >175 doublings without chromosomal aberrations or attenuation of G(2 )checkpoint function. CONCLUSION: Thus, chromosomal instability in cells with defective p53 function appears to depend upon telomere erosion not loss of the DNA damage induced G(1 )checkpoint. |
format | Text |
id | pubmed-1262734 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2005 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-12627342005-10-22 Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function Simpson, Dennis A Livanos, Elizabeth Heffernan, Timothy P Kaufmann, William K J Carcinog Research BACKGROUND: Secondary cultures of human fibroblasts display a finite lifespan ending at senescence. Loss of p53 function by mutation or viral oncogene expression bypasses senescence, allowing cell division to continue for an additional 10 – 20 doublings. During this time chromosomal aberrations seen in mitotic cells increase while DNA damage and decatenation checkpoint functions in G(2 )cells decrease. METHODS: To explore this complex interplay between chromosomal instability and checkpoint dysfunction, human fibroblast lines were derived that expressed HPV16E6 oncoprotein or dominant-negative alleles of p53 (A143V and H179Q) with or without the catalytic subunit of telomerase. RESULTS: Cells with normal p53 function displayed 86 – 93% G(1 )arrest after exposure to 1.5 Gy ionizing radiation (IR). Expression of HPV16E6 or p53-H179Q severely attenuated G(1 )checkpoint function (3 – 20% arrest) while p53-A143V expression induced intermediate attenuation (55 – 57% arrest) irrespective of telomerase expression. All cell lines, regardless of telomerase expression or p53 status, exhibited a normal DNA damage G(2 )checkpoint response following exposure to 1.5 Gy IR prior to the senescence checkpoint. As telomerase-negative cells bypassed senescence, the frequencies of chromosomal aberrations increased generally congruent with attenuation of G(2 )checkpoint function. Telomerase expression allowed cells with defective p53 function to grow >175 doublings without chromosomal aberrations or attenuation of G(2 )checkpoint function. CONCLUSION: Thus, chromosomal instability in cells with defective p53 function appears to depend upon telomere erosion not loss of the DNA damage induced G(1 )checkpoint. BioMed Central 2005-10-06 /pmc/articles/PMC1262734/ /pubmed/16209708 http://dx.doi.org/10.1186/1477-3163-4-18 Text en Copyright © 2005 Simpson et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Simpson, Dennis A Livanos, Elizabeth Heffernan, Timothy P Kaufmann, William K Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function |
title | Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function |
title_full | Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function |
title_fullStr | Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function |
title_full_unstemmed | Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function |
title_short | Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function |
title_sort | telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent g(1 )checkpoint function |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1262734/ https://www.ncbi.nlm.nih.gov/pubmed/16209708 http://dx.doi.org/10.1186/1477-3163-4-18 |
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