Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, British Columbia, V6T 1Z4, Canada.
Terry Fox Laboratory, BC Cancer Research Institute, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada.
G3 (Bethesda). 2024 May 7;14(5). doi: 10.1093/g3journal/jkae052.
DDX11/Chl1R is a conserved DNA helicase with roles in genome maintenance, DNA replication, and chromatid cohesion. Loss of DDX11 in humans leads to the rare cohesinopathy Warsaw breakage syndrome. DDX11 has also been implicated in human cancer where it has been proposed to have an oncogenic role and possibly to constitute a therapeutic target. Given the multiple roles of DDX11 in genome stability and its potential as an anticancer target, we set out to define a complete genetic interaction profile of DDX11 loss in human cell lines. Screening the human genome with clustered regularly interspaced short palindromic repeats (CRISPR) guide RNA drop out screens in DDX11-wildtype (WT) or DDX11-deficient cells revealed a strong enrichment of genes with functions related to sister chromatid cohesion. We confirm synthetic lethal relationships between DDX11 and the tumor suppressor cohesin subunit STAG2, which is frequently mutated in several cancer types and the kinase HASPIN. This screen highlights the importance of cohesion in cells lacking DDX11 and suggests DDX11 may be a therapeutic target for tumors with mutations in STAG2.
DDX11/Chl1R 是一种保守的 DNA 解旋酶，在基因组维护、DNA 复制和染色单体凝聚中发挥作用。人类中 DDX11 的缺失导致罕见的黏连蛋白病变华沙断裂综合征。DDX11 也与人类癌症有关，有人提出它具有致癌作用，并可能构成治疗靶点。鉴于 DDX11 在基因组稳定性中的多种作用及其作为抗癌靶标的潜力，我们着手定义 DDX11 在人类细胞系中缺失的完整遗传相互作用谱。在 DDX11 野生型（WT）或 DDX11 缺陷型细胞中用成簇规律间隔短回文重复（CRISPR）指导 RNA 缺失筛选对人类基因组进行筛选，发现与姐妹染色单体凝聚功能相关的基因明显富集。我们证实了 DDX11 与肿瘤抑制因子黏连蛋白亚基 STAG2 之间的合成致死关系，STAG2 在多种癌症类型中经常发生突变，以及激酶 HASPIN。该筛选强调了在缺乏 DDX11 的细胞中凝聚的重要性，并表明 DDX11 可能是 STAG2 突变肿瘤的治疗靶点。
