Targeted and Persistent 8-Oxoguanine Base Damage at Telomeres Promotes Telomere Loss and Crisis
Open accessAbstract
Telomeres are essential for genome stability. Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere shortening. Although telomeres are hypersensitive to ROS-mediated 8-oxoguanine (8-oxoG) formation, the biological effect of this common lesion at telomeres is poorly understood because ROS have pleiotropic effects. Here we developed a chemoptogenetic tool that selectively produces 8-oxoG only at telomeres. Acute telomeric 8-oxoG formation increased telomere fragility in cells lacking OGG1, the enzyme that removes 8-oxoG, but did not compromise cell survival. However, chronic telomeric 8-oxoG induction over time shortens telomeres and impairs cell growth. Accumulation of telomeric 8-oxoG in chronically exposed OGG1-deficient cells triggers replication stress, as evidenced by mitotic DNA synthesis at telomeres, and significantly increases telomere losses. These losses generate chromosome fusions, leading to chromatin bridges and micronucleus formation upon cell division. By confining base damage to the telomeres, we show that telomeric 8-oxoG accumulation directly drives telomere crisis.
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Oxidative stress induces tDD without telomere shortening and accelerates telomere shortening by inhibiting telomerase and disrupting recognition by telomere-binding proteins, contributing to uncapping.
“Oxidative stress reportedly both induces tDD without telomere shortening and accelerates telomere shortening23–26 by inhibiting telomerase27 and disrupting the recognition by telomere-binding proteins, which contributes to telomere uncapping22,28.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [23]
The Results section (page unavailable) says oxidative lesions can disrupt TRF1 and TRF2 binding in vitro and that TRF2 loss causes telomere deprotection, supporting the binding-and-uncapping portion associated with this citation. But this paper did not establish that its induced damage uncapped telomeres: it found no TRF2 loss or substantial increase in telomere-dysfunction markers. The separate shortening and telomerase clauses have other citations in the printed sentence. (LLM, conf=0.86)
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- Authors
- Fouquerel, E., Barnes, R. P., Uttam, S., Watkins, S. C., Bruchez, M. P., & Opresko, P. L.
- Affiliations
- University of Pittsburgh (US)
- Carnegie Mellon University (US)
- Corresponding author
- Opresko, Patricia L.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 75
- Issue
- 1
- Pages
- 117-130.e6
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6625854
- OpenAlex
- W2946740283
- Cited by
- 275
- References
- 81
- Citations by year
- 2026: 22 · 2025: 44 · 2024: 35 · 2023: 38 · 2022: 45 · 2021: 41 · 2020: 38 · 2019: 12
- FWCI
- 23.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- 8-oxoguanine, telomeres, telomere crisis, telomere shortening, reactive oxygen species, oxidative stress, OGG1, base damage, replication stress, chromosome fusion, chromatin bridges, micronuclei, genome stability
- MeSH terms
- Cell Division, Cell Survival, Chromosome Aberrations, DNA Damage, DNA Repair, DNA Replication, Guanine, HeLa Cells, Humans, Light, Osteoblasts, Gene Expression, Telomere, Oxidative Stress, Singlet Oxygen, Genomic Instability, DNA Glycosylases, Cell Line, Tumor, Micronuclei, Chromosome-Defective, Telomere Homeostasis, Optogenetics
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