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Mechanism of tandem duplication formation in BRCA1-mutant cells.

Authors
  • Willis, Nicholas A1
  • Frock, Richard L2
  • Menghi, Francesca3
  • Duffey, Erin E1
  • Panday, Arvind1
  • Camacho, Virginia4
  • Hasty, E Paul5
  • Liu, Edison T3, 6
  • Alt, Frederick W2
  • Scully, Ralph1
  • 1 Department of Medicine, Division of Hematology-Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. , (Israel)
  • 2 Boston Children's Hospital, Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
  • 3 The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
  • 4 Department of Medicine, Flow Cytometry Core, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. , (Israel)
  • 5 The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
  • 6 The Jackson Laboratory, Bar Harbor, Maine, USA.
Type
Published Article
Journal
Nature
Publisher
Springer Nature
Publication Date
Nov 30, 2017
Volume
551
Issue
7682
Pages
590–595
Identifiers
DOI: 10.1038/nature24477
PMID: 29168504
Source
Medline
License
Unknown

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.

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