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Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair

Telomeric repeats preserve genome integrity by stabilizing chromosomes, a function that appears to be important for both cancer and aging. In view of this critical role in genomic integrity, the telomere's own integrity should be of paramount importance to the cell. Ultraviolet light (UV), the...

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Detalles Bibliográficos
Autores principales: Rochette, Patrick J., Brash, Douglas E.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861706/
https://www.ncbi.nlm.nih.gov/pubmed/20442874
http://dx.doi.org/10.1371/journal.pgen.1000926
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author Rochette, Patrick J.
Brash, Douglas E.
author_facet Rochette, Patrick J.
Brash, Douglas E.
author_sort Rochette, Patrick J.
collection PubMed
description Telomeric repeats preserve genome integrity by stabilizing chromosomes, a function that appears to be important for both cancer and aging. In view of this critical role in genomic integrity, the telomere's own integrity should be of paramount importance to the cell. Ultraviolet light (UV), the preeminent risk factor in skin cancer development, induces mainly cyclobutane pyrimidine dimers (CPD) which are both mutagenic and lethal. The human telomeric repeat unit (5′TTAGGG/CCCTAA3′) is nearly optimal for acquiring UV-induced CPD, which form at dipyrimidine sites. We developed a ChIP–based technique, immunoprecipitation of DNA damage (IPoD), to simultaneously study DNA damage and repair in the telomere and in the coding regions of p53, 28S rDNA, and mitochondrial DNA. We find that human telomeres in vivo are 7-fold hypersensitive to UV-induced DNA damage. In double-stranded oligonucleotides, this hypersensitivity is a property of both telomeric and non-telomeric repeats; in a series of telomeric repeat oligonucleotides, a phase change conferring UV-sensitivity occurs above 4 repeats. Furthermore, CPD removal in the telomere is almost absent, matching the rate in mitochondria known to lack nucleotide excision repair. Cells containing persistent high levels of telomeric CPDs nevertheless proliferate, and chronic UV irradiation of cells does not accelerate telomere shortening. Telomeres are therefore unique in at least three respects: their biophysical UV sensitivity, their prevention of excision repair, and their tolerance of unrepaired lesions. Utilizing a lesion-tolerance strategy rather than repair would prevent double-strand breaks at closely-opposed excision repair sites on opposite strands of a damage-hypersensitive repeat.
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spelling pubmed-28617062010-05-04 Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair Rochette, Patrick J. Brash, Douglas E. PLoS Genet Research Article Telomeric repeats preserve genome integrity by stabilizing chromosomes, a function that appears to be important for both cancer and aging. In view of this critical role in genomic integrity, the telomere's own integrity should be of paramount importance to the cell. Ultraviolet light (UV), the preeminent risk factor in skin cancer development, induces mainly cyclobutane pyrimidine dimers (CPD) which are both mutagenic and lethal. The human telomeric repeat unit (5′TTAGGG/CCCTAA3′) is nearly optimal for acquiring UV-induced CPD, which form at dipyrimidine sites. We developed a ChIP–based technique, immunoprecipitation of DNA damage (IPoD), to simultaneously study DNA damage and repair in the telomere and in the coding regions of p53, 28S rDNA, and mitochondrial DNA. We find that human telomeres in vivo are 7-fold hypersensitive to UV-induced DNA damage. In double-stranded oligonucleotides, this hypersensitivity is a property of both telomeric and non-telomeric repeats; in a series of telomeric repeat oligonucleotides, a phase change conferring UV-sensitivity occurs above 4 repeats. Furthermore, CPD removal in the telomere is almost absent, matching the rate in mitochondria known to lack nucleotide excision repair. Cells containing persistent high levels of telomeric CPDs nevertheless proliferate, and chronic UV irradiation of cells does not accelerate telomere shortening. Telomeres are therefore unique in at least three respects: their biophysical UV sensitivity, their prevention of excision repair, and their tolerance of unrepaired lesions. Utilizing a lesion-tolerance strategy rather than repair would prevent double-strand breaks at closely-opposed excision repair sites on opposite strands of a damage-hypersensitive repeat. Public Library of Science 2010-04-29 /pmc/articles/PMC2861706/ /pubmed/20442874 http://dx.doi.org/10.1371/journal.pgen.1000926 Text en Rochette, Brash. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Rochette, Patrick J.
Brash, Douglas E.
Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair
title Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair
title_full Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair
title_fullStr Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair
title_full_unstemmed Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair
title_short Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair
title_sort human telomeres are hypersensitive to uv-induced dna damage and refractory to repair
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861706/
https://www.ncbi.nlm.nih.gov/pubmed/20442874
http://dx.doi.org/10.1371/journal.pgen.1000926
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