Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres
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The terminal t-loop structure adopted by mammalian telomeres is thought to prevent telomeres from being recognized as double-stranded DNA breaks by sequestering the 3' single-stranded G-rich overhang from exposure to the DNA damage machinery. The POT1 (protection of telomeres) protein binds the single-stranded overhang and is required for both chromosomal end protection and telomere length regulation. The mouse genome contains two POT1 orthologs, Pot1a and Pot1b. Here we show that conditional deletion of Pot1a elicits a DNA damage response at telomeres, resulting in p53-dependent replicative senescence. Pot1a-deficient cells exhibit overall telomere length and 3' overhang elongation as well as aberrant homologous recombination (HR) at telomeres, manifested as increased telomere sister chromatid exchanges and formation of telomere circles. Telomeric HR following Pot1a loss requires NBS1. Pot1a deletion also results in chromosomal instability. Our results suggest that POT1a is crucial for the maintenance of both telomere integrity and overall genomic stability.
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Loss of POT1 impairs telomere capping, showing that POT1 and TPP1 protect the single-stranded portion of telomeres.
“POT1 and TPP1 serve a role in protecting the single-stranded portion of the telomere because loss of POT1 impairs telomere capping (16)(17)(18)(19).”
From Telomeres and telomerase in cancer (2010) · cites this paper as [18]
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- Authors
- Wu, L., Multani, A. S., He, H., Cosme-Blanco, W., Deng, Y., Deng, J. M., Bachilo, O., Pathak, S., Tahara, H., Bailey, S. M., Deng, Y., Behringer, R. R., & Chang, S.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Rice University (US)
- Hiroshima University (JP)
- Colorado State University (US)
- Corresponding author
- Chang, Sandy
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 126
- Issue
- 1
- Pages
- 49-62
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2147765162
- Semantic Scholar
- 2e021d9226152ec6d9aca4dc9b4d91097f8b2561
- Cited by
- 422
- References
- 64
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 7 · 2023: 10 · 2022: 11 · 2021: 20 · 2020: 15 · 2019: 15 · 2018: 12 · 2017: 17 · 2016: 18 · 2015: 20 · 2014: 20 · 2013: 24 · 2012: 30
- FWCI
- 25.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2573 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 016672, R01CA129037, P30CA016672)
- 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
- POT1, telomeres, DNA damage checkpoint, homologous recombination, T-loop, 3' overhangs, DNA damage response, p53, replicative senescence, NBS1, sister chromatid exchange, chromosomal instability, genome stability, telomere length regulation
- MeSH terms
- Shelterin Complex, Animals, Cells, Cultured, Chromosome Aberrations, DNA Damage, DNA Repair, DNA-Binding Proteins, Nuclear Proteins, Recombination, Genetic, Sister Chromatid Exchange, Telomere, Cellular Senescence, Sequence Homology, Mice, Knockout, Cell Cycle Proteins, Genes, cdc, Protein Isoforms, Gene Silencing, Telomere-Binding Proteins, Genomic Instability, Mice
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