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PBRM1 directs PBAF to pericentromeres and protects centromere integrity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235344 | GEO | 2025/01/05

REPOSITORIES: GEO

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PBRM1 directs PBAF to pericentromeres and protects centromere integrity [CUT&RUN]

Project description: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 new player in centromere protection.

2025-01-05 | GSE235294 | GEO

PBRM1 directs PBAF to pericentromeres and protects centromere integrity [RNA-Seq]

2025-01-05 | GSE235342 | GEO

PBRM1 directs PBAF to pericentromeres and protects centromere integrity

Project description:PBRM1 directs PBAF to pericentromeres and protects centromere integrity

| PRJNA985717 | ENA

PBRM1 directs PBAF to pericentromeres and protects centromere integrity [CUT&RUN]

Project description:PBRM1 directs PBAF to pericentromeres and protects centromere integrity [CUT&RUN]

| PRJNA985660 | ENA

PBRM1 directs PBAF to pericentromeres and protects centromere integrity [RNA-Seq]

Project description:PBRM1 directs PBAF to pericentromeres and protects centromere integrity [RNA-Seq]

| PRJNA985722 | ENA

PBRM1 directs PBAF to pericentromeres and centromeres to constrain transcription and protect genome integrity

Project description:The specialized structure of the centromere is critical for effective chromosome segregation, but its repetitive nature and configuration makes it vulnerable to rearrangements. Centromere fragility can drive tumorigenesis, but protective mechanisms preventing fragility are still not fully understood. To identify core functions of the tumor suppressor PBRM1, a subunit of the PBAF remodelling complex, we created a panel of isogenic cell lines. We found that compromised centromere integrity is a general feature of cells lacking PBRM1. This defect creates a dependence on the spindle assembly checkpoint, which can be therapeutically exploited. We map the SMARCA4 subunit of PBAF across centromeric and pericentromeric chromatin and find PBRM1-dependent association with specific sequences. We further find that loss of PBRM1 leads to altered transcription of pericentromere-associated genes and transposable elements. These data identify PBAF as a protector of centromere structure with profound consequences for genome integrity.

2025-01-06 | PXD043209 | Pride