STAG2, a component of the mitotically essential cohesin complex, is highly mutated in several different tumour types, including glioblastoma and bladder cancer. Whereas cohesin has roles in many cancer-related pathways, such as chromosome instability, DNA repair and gene expression, the complex nature of cohesin function has made it difficult to determine how STAG2 loss might either promote tumorigenesis or be leveraged therapeutically across divergent cancer types. Here, we have performed whole-genome CRISPR-Cas9 screens for STAG2-dependent genetic interactions in three distinct cellular backgrounds. Surprisingly, STAG1, the paralog of STAG2, was the only negative genetic interaction that was shared across all three backgrounds. We also uncovered a paralogous synthetic lethal mechanism behind a genetic interaction between STAG2 and the iron regulatory gene IREB2 Finally, investigation of an unusually strong context-dependent genetic interaction in HAP1 cells revealed factors that could be important for alleviating cohesin loading stress. Together, our results reveal new facets of STAG2 and cohesin function across a variety of genetic contexts.

中文翻译：

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旁系同源合成致死性是癌症突变基因 STAG2 遗传依赖性的基础。


STAG2是有丝分裂必需的粘连蛋白复合物的一个组成部分，在几种不同的肿瘤类型中高度突变，包括胶质母细胞瘤和膀胱癌。尽管粘连蛋白在许多癌症相关途径中发挥作用，例如染色体不稳定、DNA 修复和基因表达，但粘连蛋白功能的复杂性使得很难确定STAG2缺失如何促进肿瘤发生或在不同癌症类型中发挥治疗作用。在这里，我们在三种不同的细胞背景中对STAG2依赖性遗传相互作用进行了全基因组 CRISPR-Cas9 筛选。令人惊讶的是， STAG1 （ STAG2的旁系同源物）是所有三种背景中唯一共有的负面遗传相互作用。我们还发现了STAG2和铁调节基因IREB2之间遗传相互作用背后的旁系同源合成致死机制。最后，对 HAP1 细胞中异常强烈的背景依赖性遗传相互作用的研究揭示了对于缓解粘连蛋白负载应激可能重要的因素。总之，我们的结果揭示了 STAG2 和粘连蛋白在各种遗传背景下功能的新方面。