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BRCA1 tumour suppression occurs via heterochromatin-mediated silencing

Author

Listed:
  • Quan Zhu

    (Laboratory of Genetics, The Salk Institute for Biological Studies)

  • Gerald M. Pao

    (Laboratory of Genetics, The Salk Institute for Biological Studies)

  • Alexis M. Huynh

    (Laboratory of Genetics, The Salk Institute for Biological Studies
    Present addresses: Department of Medicine, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, New York 10461, USA (A.M.H.); Stem Cells and Regenerative Medicine, Lerner Research Institute/Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA (H.S.).)

  • Hoonkyo Suh

    (Laboratory of Genetics, The Salk Institute for Biological Studies
    Present addresses: Department of Medicine, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, New York 10461, USA (A.M.H.); Stem Cells and Regenerative Medicine, Lerner Research Institute/Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA (H.S.).)

  • Nina Tonnu

    (Laboratory of Genetics, The Salk Institute for Biological Studies)

  • Petra M. Nederlof

    (the Netherlands Cancer Institute, 1066 CX)

  • Fred H. Gage

    (Laboratory of Genetics, The Salk Institute for Biological Studies)

  • Inder M. Verma

    (Laboratory of Genetics, The Salk Institute for Biological Studies)

Abstract

Mutations in the tumour suppressor gene BRCA1 lead to breast and/or ovarian cancer. Here we show that loss of Brca1 in mice results in transcriptional de-repression of the tandemly repeated satellite DNA. Brca1 deficiency is accompanied by a reduction of condensed DNA regions in the genome and loss of ubiquitylation of histone H2A at satellite repeats. BRCA1 binds to satellite DNA regions and ubiquitylates H2A in vivo. Ectopic expression of H2A fused to ubiquitin reverses the effects of BRCA1 loss, indicating that BRCA1 maintains heterochromatin structure via ubiquitylation of histone H2A. Satellite DNA de-repression was also observed in mouse and human BRCA1-deficient breast cancers. Ectopic expression of satellite DNA can phenocopy BRCA1 loss in centrosome amplification, cell-cycle checkpoint defects, DNA damage and genomic instability. We propose that the role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumour suppressor functions.

Suggested Citation

  • Quan Zhu & Gerald M. Pao & Alexis M. Huynh & Hoonkyo Suh & Nina Tonnu & Petra M. Nederlof & Fred H. Gage & Inder M. Verma, 2011. "BRCA1 tumour suppression occurs via heterochromatin-mediated silencing," Nature, Nature, vol. 477(7363), pages 179-184, September.
    • Handle: RePEc:nat:nature:v:477:y:2011:i:7363:d:10.1038_nature10371
    DOI: 10.1038/nature10371
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    Cited by:

    1. Weam S. Shahin & Shima O. Ebed & Scott R. Tyler & Branko Miljkovic & Soon H. Choi & Yulong Zhang & Weihong Zhou & Idil A. Evans & Charles Yeaman & John F. Engelhardt, 2023. "Redox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Daniel Salas-Lloret & Néstor García-Rodríguez & Emily Soto-Hidalgo & Lourdes González-Vinceiro & Carmen Espejo-Serrano & Lisanne Giebel & María Luisa Mateos-Martín & Arnoud H. Ru & Peter A. Veelen & P, 2024. "BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Clara Lopes Novo & Emily V. Wong & Colin Hockings & Chetan Poudel & Eleanor Sheekey & Meike Wiese & Hanneke Okkenhaug & Simon J. Boulton & Srinjan Basu & Simon Walker & Gabriele S. Kaminski Schierle &, 2022. "Satellite repeat transcripts modulate heterochromatin condensates and safeguard chromosome stability in mouse embryonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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