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PreprintCited by 51Telomeres, Telomerase, and SenescenceDNA Repair MechanismsDNA and Nucleic Acid Chemistry

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Human POT1 Prevents Severe Telomere Instability Induced by Homology Directed DNA Repair

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Glousker, Galina, Briod, Anna-Sophia, Quadroni, Manfredo, Lingner, Joachim·2020·The EMBO Journal
DOI 10.1101/2020.01.20.912642PMC PMC7705456

Preprint — published as 10.15252/embj.2020104500 · Paper page

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Abstract

SUMMARY: The evolutionarily conserved POT1 protein binds single stranded G-rich telomeric DNA and has been implicated in contributing to telomeric DNA maintenance and the suppression of DNA damage checkpoint signaling. Here, we explore human POT1 function through genetics and proteomics discovering that the complete absence of POT1 leads to severe telomere maintenance defects that had not been anticipated from previous depletion studies. Conditional deletion of POT1 in HEK293E cells gives rise to rapid telomere elongation and length heterogeneity, branched telomeric DNA structures, telomeric R-loops and telomere fragility. We determine the telomeric proteome upon POT1-loss implementing an improved telomeric chromatin isolation protocol. We identify a large set of proteins involved in nucleic acid metabolism that engage with telomeres upon POT1-loss. Inactivation of the homology directed repair machinery suppresses POT1-loss mediated telomeric DNA defects. Our results unravel as major function of human POT1 the suppression of telomere instability induced by homology directed repair.

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Metadata

Authors
Glousker, G., Briod, A.-S., Quadroni, M., & Lingner, J.
Affiliations
  • École Polytechnique Fédérale de Lausanne (CH)
  • University of Lausanne (CH)
Corresponding author
Lingner, Joachim
ORCID
Venue
The EMBO Journal
Publisher
openRxiv
Published
2020-01-20
Volume
39
Issue
23
Pages
e104500-e104500
ISSN
0261-4189 (ISSN-L)
DOI
10.1101/2020.01.20.912642
PMC
PMC7705456
OpenAlex
W3093230859
Cited by
51
References
1
Citations by year
2026: 5 · 2025: 9 · 2024: 10 · 2023: 8 · 2022: 8 · 2021: 10 · 2020: 1
FWCI
4.06
Type
journal article
Language
en
Open access
Licence
www.biorxiv.org/about/FAQ#license (vor)
Locations
  • The EMBO Journal (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • National Science Foundation
  • University of Texas Southwestern Medical Center
  • European Commission
  • École Polytechnique Fédérale de Lausanne
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (184718, 182880, 310030)
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
POT1, shelterin, telomere maintenance, telomere instability, homology-directed repair, telomeric DNA, telomere fragility, conditional gene deletion, DNA damage checkpoint, nucleic acid metabolism
MeSH terms
Shelterin Complex, Cell Cycle, DNA, DNA, Single-Stranded, HeLa Cells, Humans, Phenotype, Telomere, Proteome, Telomere-Binding Proteins, Gene Knockout Techniques, HEK293 Cells, Transcriptome, Recombinational DNA Repair

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