Small tandem DNA duplications result from CST-guided Pol α-primase action at DNA break termini.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34376693.
- Also identified by DOI 10.1038/s41467-021-25154-w and PMC identifier 8355091.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- DNA Breaks, Double-Stranded
- DNA Polymerase I
- DNA Primase
- Microsatellite Repeats
- Telomere-Binding Proteins