PBRM1 directs PBAF to pericentromeres and protects centromere integrity

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. Choudhary and Jessica A. Downs ()
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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
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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57277-9

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