Mechanism of tandem duplication formation in BRCA1-mutant cells.
Document Type
Article
Publication Date
11-30-2017
JAX Source
Nature 2017 Nov 30; 551(7682):590-595
Volume
551
Issue
7682
First Page
590
Last Page
595
ISSN
1476-4687
PMID
29168504
DOI
https://doi.org/10.1038/nature24477
Grant
CA034196, BC160172
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. Nature 2017 Nov 30; 551(7682):590-595.
Recommended Citation
Willis N,
Frock R,
Menghi F,
Duffey E,
Panday A,
Camacho V,
Hasty E,
Liu E,
Alt F,
Scully R.
Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature 2017 Nov 30; 551(7682):590-595