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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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Autores principales: Simpson, Dennis A, Livanos, Elizabeth, Heffernan, Timothy P, Kaufmann, William K
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2005
Materias:
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.
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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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