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Human shelterin protein POT 1 prevents severe telomere instability induced by homology‐directed DNA repair
Author(s) -
Glousker Galina,
Briod AnnaSophia,
Quadroni Manfredo,
Lingner Joachim
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020104500
Subject(s) - shelterin , telomere , telomere binding protein , genome instability , biology , dna damage , dna repair , chromatin , g2 m dna damage checkpoint , microbiology and biotechnology , dna , genetics , dna binding protein , cell cycle , gene , cell cycle checkpoint , transcription factor
The evolutionarily conserved POT 1 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 POT 1 function through genetics and proteomics, discovering that a complete absence of POT 1 leads to severe telomere maintenance defects that had not been anticipated from previous depletion studies in human cells. Conditional deletion of POT 1 in HEK 293E 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 POT 1‐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 POT 1‐loss. Inactivation of the homology‐directed repair machinery suppresses POT 1‐loss‐mediated telomeric DNA defects. Our results unravel as major function of human POT 1 the suppression of telomere instability induced by homology‐directed repair.