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Small tandem DNA duplications result from CST-guided Pol α-primase action at DNA break termini

Author

Listed:
  • Joost Schimmel

    (Leiden University Medical Center)

  • Núria Muñoz-Subirana

    (Leiden University Medical Center)

  • Hanneke Kool

    (Leiden University Medical Center)

  • Robin Schendel

    (Leiden University Medical Center)

  • Marcel Tijsterman

    (Leiden University Medical Center
    Leiden University)

Abstract

Small tandem duplications of DNA occur frequently in the human genome and are implicated in the aetiology of certain human cancers. Recent studies have suggested that DNA double-strand breaks are causal to this mutational class, but the underlying mechanism remains elusive. Here, we identify a crucial role for DNA polymerase α (Pol α)-primase in tandem duplication formation at breaks having complementary 3′ ssDNA protrusions. By including so-called primase deserts in CRISPR/Cas9-induced DNA break configurations, we reveal that fill-in synthesis preferentially starts at the 3′ tip, and find this activity to be dependent on 53BP1, and the CTC1-STN1-TEN1 (CST) and Shieldin complexes. This axis generates near-blunt ends specifically at DNA breaks with 3′ overhangs, which are subsequently repaired by non-homologous end-joining. Our study provides a mechanistic explanation for a mutational signature abundantly observed in the genomes of species and cancer cells.

Suggested Citation

  • Joost Schimmel & Núria Muñoz-Subirana & Hanneke Kool & Robin Schendel & Marcel Tijsterman, 2021. "Small tandem DNA duplications result from CST-guided Pol α-primase action at DNA break termini," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25154-w
    DOI: 10.1038/s41467-021-25154-w
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    Cited by:

    1. Sébastien Levesque & Diana Mayorga & Jean-Philippe Fiset & Claudia Goupil & Alexis Duringer & Andréanne Loiselle & Eva Bouchard & Daniel Agudelo & Yannick Doyon, 2022. "Marker-free co-selection for successive rounds of prime editing in human cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Inés Paniagua & Zainab Tayeh & Mattia Falcone & Santiago Hernández Pérez & Aurora Cerutti & Jacqueline J. L. Jacobs, 2022. "MAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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