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Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition

BACKGROUND: Telomeres, the physical ends of chromosomes, play an important role in preserving genomic integrity. This protection is supported by telomere binding proteins collectively known as the shelterin complex. The shelterin complex protects chromosome ends by suppressing DNA damage response an...

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Autores principales: Yasaei, Hemad, Gozaly-Chianea, Yaghoub, Slijepcevic, Predrag
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614538/
https://www.ncbi.nlm.nih.gov/pubmed/23521760
http://dx.doi.org/10.1186/2041-9414-4-2
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author Yasaei, Hemad
Gozaly-Chianea, Yaghoub
Slijepcevic, Predrag
author_facet Yasaei, Hemad
Gozaly-Chianea, Yaghoub
Slijepcevic, Predrag
author_sort Yasaei, Hemad
collection PubMed
description BACKGROUND: Telomeres, the physical ends of chromosomes, play an important role in preserving genomic integrity. This protection is supported by telomere binding proteins collectively known as the shelterin complex. The shelterin complex protects chromosome ends by suppressing DNA damage response and acting as a regulator of telomere length maintenance by telomerase, an enzyme that elongates telomeres. Telomere dysfunction manifests in different forms including chromosomal end-to-end fusion, telomere shortening and p53-dependent apoptosis and/or senescence. An important shelterin-associated protein with critical role in telomere protection in human and mouse cells is the catalytic subunit of DNA-protein kinase (DNA-PKcs). DNA-PKcs deficiency in mouse cells results in elevated levels of spontaneous telomeric fusion, a marker of telomere dysfunction, but does not cause telomere length shortening. Similarly, inhibition of DNA-PKcs with chemical inhibitor, IC86621, prevents chromosomal end protection through mechanism reminiscent of dominant-negative reduction in DNA-PKcs activity. RESULTS: We demonstrate here that the IC86621 mediated inhibition of DNA-PKcs in two mouse lymphoma cell lines results not only in elevated frequencies of chromosome end-to-end fusions, but also accelerated telomere shortening in the presence of telomerase. Furthermore, we observed increased levels of spontaneous telomeric fusions in Artemis defective human primary fibroblasts in which DNA-PKcs was inhibited, but no significant changes in telomere length. CONCLUSION: These results confirm that DNA-PKcs plays an active role in chromosome end protection in mouse and human cells. Furthermore, it appears that DNA-PKcs is also involved in telomere length regulation, independently of telomerase activity, in mouse lymphoma cells but not in human cells.
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spelling pubmed-36145382013-04-03 Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition Yasaei, Hemad Gozaly-Chianea, Yaghoub Slijepcevic, Predrag Genome Integr Research BACKGROUND: Telomeres, the physical ends of chromosomes, play an important role in preserving genomic integrity. This protection is supported by telomere binding proteins collectively known as the shelterin complex. The shelterin complex protects chromosome ends by suppressing DNA damage response and acting as a regulator of telomere length maintenance by telomerase, an enzyme that elongates telomeres. Telomere dysfunction manifests in different forms including chromosomal end-to-end fusion, telomere shortening and p53-dependent apoptosis and/or senescence. An important shelterin-associated protein with critical role in telomere protection in human and mouse cells is the catalytic subunit of DNA-protein kinase (DNA-PKcs). DNA-PKcs deficiency in mouse cells results in elevated levels of spontaneous telomeric fusion, a marker of telomere dysfunction, but does not cause telomere length shortening. Similarly, inhibition of DNA-PKcs with chemical inhibitor, IC86621, prevents chromosomal end protection through mechanism reminiscent of dominant-negative reduction in DNA-PKcs activity. RESULTS: We demonstrate here that the IC86621 mediated inhibition of DNA-PKcs in two mouse lymphoma cell lines results not only in elevated frequencies of chromosome end-to-end fusions, but also accelerated telomere shortening in the presence of telomerase. Furthermore, we observed increased levels of spontaneous telomeric fusions in Artemis defective human primary fibroblasts in which DNA-PKcs was inhibited, but no significant changes in telomere length. CONCLUSION: These results confirm that DNA-PKcs plays an active role in chromosome end protection in mouse and human cells. Furthermore, it appears that DNA-PKcs is also involved in telomere length regulation, independently of telomerase activity, in mouse lymphoma cells but not in human cells. BioMed Central 2013-03-22 /pmc/articles/PMC3614538/ /pubmed/23521760 http://dx.doi.org/10.1186/2041-9414-4-2 Text en Copyright © 2013 Yasaei 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
Yasaei, Hemad
Gozaly-Chianea, Yaghoub
Slijepcevic, Predrag
Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition
title Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition
title_full Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition
title_fullStr Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition
title_full_unstemmed Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition
title_short Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition
title_sort analysis of telomere length and function in radiosensitive mouse and human cells in response to dna-pkcs inhibition
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614538/
https://www.ncbi.nlm.nih.gov/pubmed/23521760
http://dx.doi.org/10.1186/2041-9414-4-2
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