Mechanism of tandem duplication formation in BRCA1-mutant cells

Nicholas A. Willis, Richard L. Frock, Francesca Menghi, Erin E. Duffey, Arvind Panday, Virginia Camacho, E. Paul Hasty, Edison T. Liu, Frederick W. Alt, Ralph Scully

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)590-595
Number of pages6
JournalNature
Volume551
Issue number7682
DOIs
StatePublished - Nov 30 2017

ASJC Scopus subject areas

  • General

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