Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project^1,2,3. We report that the little-studied gene DDB1–CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

虽然癌基因可能会被小分子抑制，但肿瘤抑制因子的丢失更为常见，并且会产生问题，因为肿瘤抑制蛋白不再存在以供靶向。值得注意的例子包括SMARCB1突变癌症，这是由 SWI/SNF（也称为 BAF）染色质重塑复合物亚基失活引起的高度致命的恶性肿瘤。在这里，为了深入了解 SMARCB1 突变的后果并识别漏洞，我们将 14 个SMARCB1突变细胞系贡献给近基因组范围的 CRISPR 筛选，作为癌症依赖性图项目的一部分^1,2,3。我们报告说，很少研究的基因 DDB1–CUL4 相关因子 5 ( DCAF5 ) 是SMARCB1突变癌症的生存所必需的。我们证明 DCAF5 对 SWI/SNF 复合物具有质量控制功能，并在 SMARCB1 缺失的情况下促进不完全组装的 SWI/SNF 复合物的降解。 DCAF5耗尽后，SMARCB1缺陷的SWI/SNF复合物重新积累，与靶位点结合，并将SWI/SNF介导的基因表达恢复到足以逆转癌症状态的水平，包括在体内。因此，癌症并不是由 SMARCB1 功能本身丧失引起的，而是由 DCAF5 介导的 SWI/SNF 复合物降解引起的。这些数据表明，针对泛素介导的质量控制因子的治疗靶向可以有效逆转由肿瘤抑制复合物破坏引起的某些癌症的恶性状态。