Mechanism of tandem duplication formation in BRCA1-mutant cells.
Nature, 2017/11/30;551(7682):590-595.
Willis NA[1], Frock RL[2], Menghi F[3], Duffey EE[1], Panday A[1], Camacho V[4], Hasty EP[5], Liu ET[3, 6], Alt FW[2], Scully R[1]
Affiliations
PMID: 29168504DOI: 10.1038/nature24477
Impact factor: 69.504
Abstract
Small, approximately 10-kilobase microhomology-mediated tandem duplications are abundant in the genomes of BRCA1-linked but not BRCA2-linked breast cancer. Here we define the mechanism underlying this rearrangement signature. We show that, in primary mammalian cells, BRCA1, but not BRCA2, suppresses the formation of tandem duplications at a site-specific chromosomal replication fork barrier imposed by the binding of Tus proteins to an array of Ter sites. BRCA1 has no equivalent role at chromosomal double-stranded DNA breaks, indicating that tandem duplications form specifically at stalled forks. Tandem duplications in BRCA1 mutant cells arise by a replication restart-bypass mechanism terminated by end joining or by microhomology-mediated template switching, the latter forming complex tandem duplication breakpoints. Solitary DNA ends form directly at Tus-Ter, implicating misrepair of these lesions in tandem duplication formation. Furthermore, BRCA1 inactivation is strongly associated with ~10 kilobase tandem duplications in ovarian cancer. This tandem duplicator phenotype may be a general signature of BRCA1-deficient cancer.
MeSH terms
Animals; BRCA1 Protein; Cells, Cultured; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; DNA Replication; Embryonic Stem Cells; Female; Genes, Reporter; Homologous Recombination; Humans; Mice; Ovarian Neoplasms; Sequence Deletion; Tandem Repeat Sequences; Tumor Suppressor Proteins
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