Small tandem dna duplications result from cst-guided pol α-primase action at dna break termini
| Autor: | Hanneke Kool, Robin van Schendel, Joost Schimmel, Núria Muñoz-Subirana, Marcel Tijsterman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA End-Joining Repair
DNA polymerase Science Telomere-Binding Proteins DNA Single-Stranded General Physics and Astronomy Double-strand DNA breaks Cell Cycle Proteins DNA Primase medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology Cell Line Mice chemistry.chemical_compound medicine Animals Humans CRISPR DNA Breaks Double-Stranded Non-homologous-end joining Cells Cultured Mutation Multidisciplinary Base Sequence biology General Chemistry Telomere DNA Polymerase I Cell biology DNA-Binding Proteins Non-homologous end joining chemistry Multiprotein Complexes biology.protein Human genome Primase Tumor Suppressor p53-Binding Protein 1 DNA Microsatellite Repeats |
| Zdroj: | Nature Communications, 12(1) Nature Communications, Vol 12, Iss 1, Pp 1-11 (2021) Nature Communications Nature Communications, 12(1). NATURE PORTFOLIO |
| Popis: | 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. Error-prone repair of DNA double-strand breaks have been implied to cause cancer-associated genome alterations, but the mechanism of their formation remains unclear. Here the authors find that DNA polymerase α primase plays part in tandem duplication formation at CRISPR/Cas9-induced complementary 3′ ssDNA protrusions. |
| Databáze: | OpenAIRE |
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