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 and Ralph Scully ()
Additional contact information
Nicholas A. Willis: Beth Israel Deaconess Medical Center and Harvard Medical School
Richard L. Frock: Boston Children’s Hospital, Harvard Medical School
Francesca Menghi: The Jackson Laboratory for Genomic Medicine
Erin E. Duffey: Beth Israel Deaconess Medical Center and Harvard Medical School
Arvind Panday: Beth Israel Deaconess Medical Center and Harvard Medical School
Virginia Camacho: Flow Cytometry Core, Beth Israel Deaconess Medical Center
E. Paul Hasty: The University of Texas Health Science Center at San Antonio
Edison T. Liu: The Jackson Laboratory for Genomic Medicine
Frederick W. Alt: Boston Children’s Hospital, Harvard Medical School
Ralph Scully: Beth Israel Deaconess Medical Center and Harvard Medical School

Nature, 2017, vol. 551, issue 7682, 590-595

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/nature24477 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:551:y:2017:i:7682:d:10.1038_nature24477

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature24477

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().