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

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.

着丝粒（centromere）的特殊结构对于高效染色体分离至关重要，但其重复序列属性与空间构型使其极易发生染色体重排。着丝粒脆性（centromere fragility）可促进肿瘤发生，但目前针对该脆性的保护机制仍未完全阐明。为明确肿瘤抑制因子PBRM1——PBAF染色质重塑复合物的一个亚基——的核心功能，我们构建了一组同基因细胞系（isogenic cell lines）。研究发现，PBRM1缺失的细胞普遍存在着丝粒完整性受损的表型。该缺陷会使细胞依赖纺锤体组装检查点（spindle assembly checkpoint），这一特性可被用于治疗靶向。我们对PBAF的SMARCA4亚基在着丝粒及着丝粒旁染色质上的结合分布进行了图谱绘制，发现其与特定序列的结合依赖PBRM1。进一步研究表明，PBRM1缺失会改变着丝粒旁相关基因与转座因子（transposable elements）的转录水平。上述数据证实，PBAF是维持着丝粒结构的保护因子，其功能异常会对基因组完整性产生深远影响。