Human Telomeres Are Hypersensitive to UV-Induced DNA Damage and Refractory to Repair
Open accessAbstract
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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Photoreactions are enhanced in telomeres, with possible interstrand lesion formation in the quadruplex region.
“Evidence has also been provided for the enhanced efficiency of photoreactions in telomeres (70) with the possible formation of interstrand lesions in the quadruplex region (71).”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [70]
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Self-citation
- Authors
- Rochette, P. J., & Brash, D. E.
- Affiliations
- Yale Cancer Center (US)
- Corresponding author
- Brash, Douglas E.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-04-29
- Volume
- 6
- Issue
- 4
- Pages
- e1000926
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC2861706
- OpenAlex
- W2020449338
- Cited by
- 133
- References
- 50
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 13 · 2020: 6 · 2019: 8 · 2018: 3 · 2017: 8 · 2016: 10 · 2015: 7 · 2014: 14 · 2013: 8 · 2012: 16
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Fonds de Recherche du Québec - Santé
- National Cancer Institute (R01CA055737, CA55737)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- telomeres, ultraviolet radiation, cyclobutane pyrimidine dimers, DNA damage hypersensitivity, nucleotide excision repair, telomere shortening, iPod, mitochondrial DNA, p53, 28S rDNA, skin cancer, genome stability
- MeSH terms
- Adult, DNA, DNA Damage, DNA Repair, Female, Humans, Ultraviolet Rays, Telomere
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