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Mechanism of tandem duplication formation in BRCA1-mutant cells

Author

Listed:
  • 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
    The Jackson Laboratory)

  • Frederick W. Alt

    (Boston Children’s Hospital, Harvard Medical School)

  • Ralph Scully

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

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.

Suggested Citation

  • 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, 2017. "Mechanism of tandem duplication formation in BRCA1-mutant cells," Nature, Nature, vol. 551(7682), pages 590-595, November.
    • Handle: RePEc:nat:nature:v:551:y:2017:i:7682:d:10.1038_nature24477
    DOI: 10.1038/nature24477
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    Cited by:

    1. Lorenzo Corazzi & Vivien S. Ionasz & Sergej Andrejev & Li-Chin Wang & Athanasios Vouzas & Marco Giaisi & Giulia Di Muzio & Boyu Ding & Anna J. M. Marx & Jonas Henkenjohann & Michael M. Allers & David , 2024. "Linear interaction between replication and transcription shapes DNA break dynamics at recurrent DNA break Clusters," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Adam C. Weiner & Marc J. Williams & Hongyu Shi & Ignacio Vázquez-García & Sohrab Salehi & Nicole Rusk & Samuel Aparicio & Sohrab P. Shah & Andrew McPherson, 2024. "Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Yi-Li Feng & Qian Liu & Ruo-Dan Chen & Si-Cheng Liu & Zhi-Cheng Huang & Kun-Ming Liu & Xiao-Ying Yang & An-Yong Xie, 2022. "DNA nicks induce mutational signatures associated with BRCA1 deficiency," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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