DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion
Abstract
Telomere attrition and other forms of telomere damage can activate the ATM kinase pathway. What generates the DNA damage signal at mammalian chromosome ends or at other double-strand breaks is not known. Telomere dysfunction is often accompanied by disappearance of the 3' telomeric overhang, raising the possibility that DNA degradation could generate the structure that signals. Here we address these issues by studying telomere structure after conditional deletion of mouse TRF2, the protective factor at telomeres. Upon removal of TRF2 from TRF2(F/-) p53-/- mouse embryo fibroblasts, a telomere damage response is observed at most chromosome ends. As expected, the telomeres lose the 3' overhang and are processed by the non-homologous end-joining pathway. Non-homologous end joining of telomeres was abrogated in DNA ligase IV-deficient (Lig4-/-) cells. Unexpectedly, the telomeres of TRF2-/- Lig4-/- p53-/- cells persisted in a free state without undergoing detectable DNA degradation. Notably, the telomeres retained their 3' overhangs, but they were recognized as sites of DNA damage, accumulating the DNA damage response factors 53BP1 and gamma-H2AX, and activating the ATM kinase. Thus, activation of the ATM kinase pathway at chromosome ends does not require overhang degradation or other overt DNA processing.
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When telomeres are compromised by loss of TRF2, their repair is carried out by c-NHEJ.
“By contrast, when telomeres are compromised through the loss of TRF2, their repair is carried out by c-NHEJ80–82.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [81]
Acute telomere deprotection by inactivation of the shelterin protein TRF2 leads to robust telomeric ATM signaling, NHEJ-dependent telomere end-to-end fusion, and rapid cell cycle arrest.
“Similarly, acute telomere deprotection by inactivation of the shelterin protein TRF2 leads to robust telomeric ATM signaling, NHEJ-dependent telomere end-to-end fusion, and rapid cell cycle arrest [71,95].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [95]
TRF2 is essential for protecting telomere ends and can promote t-loop formation.
“TRF2 is critical for telomere end protection and can facilitate formation of the t-loop conformation.”
From Telomeres and telomerase in cancer (2010) · cites this paper as [4]
When TRF2 is disrupted, the protective capped structure is lost, the 3' overhang is processed, and chromosome ends become ligated.
“Disruption of TRF2 through overexpression of a dominant-negative form or through deletion in TRF2-knockout mouse embryo fibroblasts leads to loss of the protective capped structure, characterized by processing of the 3# overhang and ligation of chromosome ends (3,4).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [4]
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- Authors
- Celli, G. B., & de Lange, T.
- Affiliations
- NYU Langone Health (US)
- Venue
- Nature Cell Biology
- Published
- 2005-06-19
- Volume
- 7
- Issue
- 7
- Pages
- 712-718
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2035389897
- Semantic Scholar
- f4e3c6cbe3167cb507269beefcc7ad01ad45332d
- Cited by
- 623
- References
- 36
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 28 · 2023: 19 · 2022: 16 · 2021: 27 · 2020: 26 · 2019: 20 · 2018: 22 · 2017: 37 · 2016: 24 · 2015: 37 · 2014: 41 · 2013: 37 · 2012: 41
- FWCI
- 20.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM49046-12)
- 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
- ATM kinase, TRF2, telomere shortening, non-homologous end joining, DNA ligase IV, DNA damage signaling, 53BP1, γH2AX, telomere dysfunction, p53-deficient cells
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, DNA Ligase ATP, Animals, Cells, Cultured, Chromosomal Proteins, Non-Histone, Crosses, Genetic, DNA, DNA Damage, DNA-Binding Proteins, Embryo, Mammalian, Fibroblasts, Histones, Mice, Transgenic, Phosphoproteins, Phosphorylation, DNA Ligases, Transfection, Tumor Suppressor Protein p53, Telomere, Protein Serine-Threonine Kinases, Gene Deletion, In Situ Hybridization, Fluorescence, Mice, Knockout, Cell Cycle Proteins, rap1 GTP-Binding Proteins, Tumor Suppressor Proteins, Telomeric Repeat Binding Protein 1, Telomeric Repeat Binding Protein 2, Intracellular Signaling Peptides and Proteins, Mice, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
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