期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-25154-w
关键词
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资金
- Young Investigator Grant from the Dutch Cancer Society (KWF) [2020-1/12925]
- Veni-grant from The Netherlands Organization for Scientific Research for Earth and Life Sciences [016.Veni.171.028]
- Dutch Cancer Society [11251/2017-2]
- Holland Proton Therapy Centre [2019020-PROTONDDR]
The study identifies a crucial role for DNA polymerase alpha (Pol alpha)-primase in tandem duplication formation at breaks having complementary 3 ' ssDNA protrusions induced by CRISPR/Cas9. This mechanism provides an 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 alpha primase plays part in tandem duplication formation at CRISPR/Cas9-induced complementary 3 ' ssDNA protrusions. 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 alpha (Pol alpha)-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.
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