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A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites

Author

Listed:
  • Wouter Koole

    (Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands)

  • Robin van Schendel

    (Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands)

  • Andrea E. Karambelas

    (Hubrecht Institute—KNAW—Utrecht University Medical Center, Uppsalalaan 8, 3584 CT, The Netherlands)

  • Jane T. van Heteren

    (Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands)

  • Kristy L. Okihara

    (Hubrecht Institute—KNAW—Utrecht University Medical Center, Uppsalalaan 8, 3584 CT, The Netherlands)

  • Marcel Tijsterman

    (Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands)

Abstract

Genomes contain many sequences that are intrinsically difficult to replicate. Tracts of tandem guanines, for instance, have the potential to adopt stable G-quadruplex structures, which are prone to cause genome alterations. Here we describe G4 DNA-induced mutagenesis in Caenorhabditis elegans and identify a non-canonical DNA break repair mechanism that generates deletions characterized by an extremely narrow size distribution, minimal homology of exactly one nucleotide at the junctions, and by the occasional presence of templated insertions. This typical mutation profile is fully dependent on the A-family polymerase Theta, the absence of which leads to profound loss of sequences surrounding G4 motifs. Theta-mediated end-joining prevails over non-homologous end joining and homologous recombination and prevents genomic havoc at replication fork barriers at the expense of small deletions. G4 DNA-induced deletions also manifest in the genomes of wild isolates of C. elegans, indicating a protective role for this pathway during evolution.

Suggested Citation

  • Wouter Koole & Robin van Schendel & Andrea E. Karambelas & Jane T. van Heteren & Kristy L. Okihara & Marcel Tijsterman, 2014. "A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4216
    DOI: 10.1038/ncomms4216
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    Cited by:

    1. Fumiaki Ito & Ziyuan Li & Leonid Minakhin & Gurushankar Chandramouly & Mrityunjay Tyagi & Robert Betsch & John J. Krais & Bernadette Taberi & Umeshkumar Vekariya & Marissa Calbert & Tomasz Skorski & N, 2024. "Structural basis for a Polθ helicase small-molecule inhibitor revealed by cryo-EM," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Zhiqian Li & Lang You & Anita Hermann & Ethan Bier, 2024. "Developmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. William Fried & Mrityunjay Tyagi & Leonid Minakhin & Gurushankar Chandramouly & Taylor Tredinnick & Mercy Ramanjulu & William Auerbacher & Marissa Calbert & Timur Rusanov & Trung Hoang & Nikita Boriso, 2024. "Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. J. A. Kamp & B. B. L. G. Lemmens & R. J. Romeijn & S. C. Changoer & R. Schendel & M. Tijsterman, 2021. "Helicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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