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Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis
Open accessAbstract
The POT1 (protection of telomeres) protein binds the single-stranded G-rich overhang and is essential for both telomere end protection and telomere length regulation. Telomeric binding of POT1 is enhanced by its interaction with TPP1. In this study, we demonstrate that mouse Tpp1 confers telomere end protection by recruiting Pot1a and Pot1b to telomeres. Knockdown of Tpp1 elicits a p53-dependent growth arrest and an ATM-dependent DNA damage response at telomeres. In contrast to depletion of Trf2, which activates ATM, removal of Pot1a and Pot1b from telomeres initiates an ATR-dependent DNA damage response (DDR). Finally, we show that telomere dysfunction as a result of Tpp1 depletion promotes chromosomal instability and tumorigenesis in the absence of an ATM-dependent DDR. Our results uncover a novel ATR-dependent DDR at telomeres that is normally shielded by POT1 binding to the single-stranded G-overhang. In addition, our results suggest that loss of ATM can cooperate with dysfunctional telomeres to promote cellular transformation and tumor formation in vivo.
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“Dysfunctional telomeres activate upstream checkpoint PI3 kinases, such as ATM (ataxia-telangiectasia mutated) or ATR (ataxia-telangiectasia and Rad3 related)22, 27-30”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [27]
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Metadata
- Authors
- Guo, X., Deng, Y., Lin, Y., Cosme‐Blanco, W., Chan, S., He, H., Yuan, G., Brown, E. J., & Chang, S.
- Affiliations
- North Sichuan Medical University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- University of Pennsylvania (US)
- Corresponding author
- Deng, Yibin
- Chang, Sandy
- Venue
- The EMBO Journal
- Published
- 2007-10-18
- Volume
- 26
- Issue
- 22
- Pages
- 4709-4719
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2080807
- OpenAlex
- W1985964699
- Cited by
- 258
- References
- 56
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 21 · 2020: 9 · 2019: 9 · 2018: 15 · 2017: 12 · 2016: 13 · 2015: 11 · 2014: 15 · 2013: 17 · 2012: 16
- FWCI
- 14.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Welch Foundation
- Elsa U. Pardee Foundation
- Sidney Kimmel Foundation for Cancer Research
- Sidney Kimmel Foundation
- Abraham J. and Phyllis Katz Foundation
- National Institute on Aging (R01AG028888)
- National Cancer Institute (K01CA124461, RO1 CA129037, R01CA129037)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
- telomere dysfunction, POT1, TPP1, ATM, ATR, DNA damage response, telomere protection, TRF2, chromosomal instability, carcinogenesis, cell transformation
- MeSH terms
- Shelterin Complex, Animals, Cells, Cultured, DNA Damage, DNA-Binding Proteins, Embryo, Mammalian, Fibroblasts, Neoplasms, RNA, Messenger, Telomere, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Telomere-Binding Proteins, Telomeric Repeat Binding Protein 2, Mice, Ataxia Telangiectasia Mutated Proteins
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