Cited by 258Telomeres, Telomerase, and SenescenceDNA Repair MechanismsDNA and Nucleic Acid Chemistry

Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis

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Guo, Xiaolan, Deng, Yibin, Lin, Yahong, Cosme‐Blanco, Wilfredo, Chan, Suzanne, He, Hua, Yuan, Guohua, Brown, Eric J +1 more·2007·The EMBO Journal

Abstract

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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Crossref · 10.1038/sj.emboj.7601893

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  • Dysfunctional telomeres activate upstream checkpoint PI3 kinases such as ATM or ATR.

    “Dysfunctional telomeres activate upstream checkpoint PI3 kinases, such as ATM (ataxia-telangiectasia mutated) or ATR (ataxia-telangiectasia and Rad3 related)22, 27-30”

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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
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
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
  • 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
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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