Synthetic lethal interaction between the tumour suppressor STAG2 and its paralog STAG1.
Synthetic lethal interaction between the tumour suppressor STAG2 and its paralog STAG1.
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DOI：
10.18632/oncotarget.16838
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发表时间：
2017-06-06
期刊：
影响因子：
--
通讯作者：
Ciccarelli FD
中科院分区：
文献类型：
--
作者：
Benedetti L;Cereda M;Monteverde L;Desai N;Ciccarelli FD
粘连蛋白是一种多蛋白复合物，在有丝分裂过程中连接姐妹染色单体并介导 DNA 修复、基因组区室化和基因表达调节。粘连蛋白亚基经常发生癌症功能丧失改变，并在多种肿瘤类型中充当肿瘤抑制因子。这导致人们对粘连蛋白作为抗癌治疗的潜在靶点越来越感兴趣。在这里，我们表明，粘连蛋白的核心成分和新兴的肿瘤抑制因子 STAG2 的功能丧失，导致突变的癌细胞对其旁系同源物 STAG1 的合成依赖。 STAG1和STAG2具有高度的序列同一性，编码互斥的粘连蛋白亚基并保留部分重叠的功能。我们在几种癌细胞系中抑制了 STAG1 和 STAG2，其中这两个基因具有可变的突变和拷贝数状态。在所有情况下，我们观察到同时阻断 STAG1 和 STAG2 会显着降低细胞增殖。我们进一步证实了合成致死相互作用，开发了无载体 CRISPR 系统来诱导 STAG1/STAG2 双基因敲除。我们提供了强有力的证据，表明 STAG1 是具有 STAG2 失活改变的癌症的一个有前途的治疗靶点。
Cohesin is a multi-protein complex that tethers sister chromatids during mitosis and mediates DNA repair, genome compartmentalisation and regulation of gene expression. Cohesin subunits frequently acquire cancer loss-of-function alterations and act as tumour suppressors in several tumour types. This has led to increased interest in cohesin as potential target in anti-cancer therapy. Here we show that the loss-of-function of STAG2, a core component of cohesin and an emerging tumour suppressor, leads to synthetic dependency of mutated cancer cells on its paralog STAG1. STAG1 and STAG2 share high sequence identity, encode mutually exclusive cohesin subunits and retain partially overlapping functions. We inhibited STAG1 and STAG2 in several cancer cell lines where the two genes have variable mutation and copy number status. In all cases, we observed that the simultaneous blocking of STAG1 and STAG2 significantly reduces cell proliferation. We further confirmed the synthetic lethal interaction developing a vector-free CRISPR system to induce STAG1/STAG2 double gene knockout. We provide strong evidence that STAG1 is a promising therapeutic target in cancers with inactivating alterations of STAG2.
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影响因子：
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通讯作者：
Benes, Cyril H.
影响因子：
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作者：
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