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

Joost Schimmel, Núria Muñoz-Subirana, Hanneke Kool, Robin Schendel and Marcel Tijsterman ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25154-w

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