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PBRM1 directs PBAF to pericentromeres and protects centromere integrity

Author

Listed:
  • Karen A. Lane

    (The Institute of Cancer Research; London)

  • Alison Harrod

    (The Institute of Cancer Research; London)

  • Lillian Wu

    (The Institute of Cancer Research; London)

  • Theodoros I. Roumeliotis

    (The Institute of Cancer Research; London)

  • Hugang Feng

    (The Institute of Cancer Research; London
    The Francis Crick Institute; London)

  • Shane Foo

    (The Institute of Cancer Research; London)

  • Katheryn A. G. Begg

    (The Institute of Cancer Research; London)

  • Federica Schiavoni

    (The Institute of Cancer Research; London)

  • Noa Amin

    (The Institute of Cancer Research; London)

  • Frank T. Zenke

    (Translational Innovation Platform Oncology)

  • Alan A. Melcher

    (The Institute of Cancer Research; London)

  • Jyoti S. Choudhary

    (The Institute of Cancer Research; London)

  • Jessica A. Downs

    (The Institute of Cancer Research; London)

Abstract

The specialised structure of the centromere is critical for effective chromosome segregation, but its repetitive nature makes it vulnerable to rearrangements. Centromere fragility can drive tumorigenesis, but protective mechanisms preventing fragility are still not fully understood. The PBAF chromatin remodelling complex is frequently misregulated in cancer, but its role in cancer is incompletely characterized. Here, we identify PBAF as a protector of centromere and pericentromere structure with profound consequences for genome stability. A conserved feature of isogenic cell lines lacking PBRM1, a subunit of PBAF, is compromised centromere and pericentromere integrity. PBAF is present at these regions, and binding patterns of PBAF and H3K9 methylation change when PBRM1 is absent. PBRM1 loss creates a dependence on the spindle assembly checkpoint, which represents a therapeutic vulnerability. Importantly, we find that even in the absence of any perturbations, PBRM1 loss leads to centromere fragility, thus identifying a key player in centromere protection.

Suggested Citation

  • Karen A. Lane & Alison Harrod & Lillian Wu & Theodoros I. Roumeliotis & Hugang Feng & Shane Foo & Katheryn A. G. Begg & Federica Schiavoni & Noa Amin & Frank T. Zenke & Alan A. Melcher & Jyoti S. Chou, 2025. "PBRM1 directs PBAF to pericentromeres and protects centromere integrity," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57277-9
    DOI: 10.1038/s41467-025-57277-9
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    References listed on IDEAS

    as
    1. V. Barra & D. Fachinetti, 2018. "The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    2. Federica Schiavoni & Pedro Zuazua-Villar & Theodoros I. Roumeliotis & Graeme Benstead-Hume & Mercedes Pardo & Frances M. G. Pearl & Jyoti S. Choudhary & Jessica A. Downs, 2022. "Aneuploidy tolerance caused by BRG1 loss allows chromosome gains and recovery of fitness," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Alexander Favorov & Loris Mularoni & Leslie M Cope & Yulia Medvedeva & Andrey A Mironov & Vsevolod J Makeev & Sarah J Wheelan, 2012. "Exploring Massive, Genome Scale Datasets with the GenometriCorr Package," PLOS Computational Biology, Public Library of Science, vol. 8(5), pages 1-12, May.
    4. Ruben M. Drews & Barbara Hernando & Maxime Tarabichi & Kerstin Haase & Tom Lesluyes & Philip S. Smith & Lena Morrill Gavarró & Dominique-Laurent Couturier & Lydia Liu & Michael Schneider & James D. Br, 2022. "A pan-cancer compendium of chromosomal instability," Nature, Nature, vol. 606(7916), pages 976-983, June.
    5. Karen A. Lane & Alison Harrod & Lillian Wu & Theodoros I. Roumeliotis & Hugang Feng & Shane Foo & Katheryn A. G. Begg & Federica Schiavoni & Noa Amin & Frank T. Zenke & Alan A. Melcher & Jyoti S. Chou, 2025. "PBRM1 directs PBAF to pericentromeres and protects centromere integrity," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
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    Cited by:

    1. Karen A. Lane & Alison Harrod & Lillian Wu & Theodoros I. Roumeliotis & Hugang Feng & Shane Foo & Katheryn A. G. Begg & Federica Schiavoni & Noa Amin & Frank T. Zenke & Alan A. Melcher & Jyoti S. Chou, 2025. "PBRM1 directs PBAF to pericentromeres and protects centromere integrity," Nature Communications, Nature, vol. 16(1), pages 1-20, December.

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