Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair
Open Access
- 29 April 2010
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 6 (4), e1000926
- https://doi.org/10.1371/journal.pgen.1000926
Abstract
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. Telomeres consist of a repeated sequence located at each end of each chromosome. This repeated sequence is required for chromosomal stability and integrity, a function important for both cancer and aging. The DNA sequence of human telomeres is 5–10 kb of a repeated double-strand hexamer (5′TTAGGG/5′CCCTAA). In theory, this sequence is nearly optimal for acquiring UV-induced DNA damage. We developed a novel technique, the immunoprecipitation of DNA damage (IPoD), to study DNA damage induction and repair in the telomere and in coding regions (p53, 28S rDNA, and mitochondrial DNA). We find that human telomeres are hypersensitive to UV-induced DNA photoproducts and that the removal of those DNA photoproducts is almost absent. Cells containing persistent high levels of telomeric DNA damage 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.Keywords
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