Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets.

中文翻译：

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非规范的SWI / SNF复合物是由BAF复合物扰动驱动的癌症的合成致死靶标。

哺乳动物SWI / SNF染色质重塑复合物以三种不同的最终形式存在：经典BAF（cBAF），PBAF和新近鉴定的非经典复合物（ncBAF）。但是，它们对染色质，疾病中的功能和作用的复合物特异性靶标在很大程度上仍然不确定。在这里，我们对染色质上的复杂装配体进行了全面定位，发现ncBAF复合体唯一地定位于CTCF位点和启动子。我们确定ncBAF亚基为特定于滑膜肉瘤和恶性横纹肌瘤的合成致死靶标，它们均表现出cBAF复合物（SMARCB1亚基）摄动。ncBAF亚基BRD9的化学和生物学耗竭迅速减弱了滑膜肉瘤和恶性横纹肌瘤细胞的增殖。重要的是，在cBAF干扰的癌症中，ncBAF复合物在保留的CTCF启动子位点维持基因表达，并以不同于融合癌蛋白结合复合物的方式发挥作用。总之，这些发现揭示了ncBAF复合物的独特靶向作用和功能作用，并提出了新的癌症特异性治疗靶标。