The RecQ DNA helicase WRN is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair 1 – 4 . Depletion of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI-associated cancers from double-strand breaks remains unclear. Here we show that TA-dinucleotide repeats are highly unstable in MSI cells and undergo large-scale expansions, distinct from previously described insertion or deletion mutations of a few nucleotides 5 . Expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and require unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 nuclease, leading to massive chromosome shattering. These findings identify a distinct biomarker that underlies the synthetic lethal dependence on WRN, and support the development of therapeutic agents that target WRN for MSI-associated cancers. In cells with microsatellite instability, expanded TA-dinucleotide repeats form cruciform structures that stall replication forks and cause chromosome shattering in the absence of the WRN helicase.

中文翻译：

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重复扩增在微卫星不稳定的癌症中赋予 WRN 依赖性

RecQ DNA 解旋酶 WRN 是具有微卫星不稳定性 (MSI) 的癌细胞的合成致命靶标，这是一种由错配修复受损引起的遗传超突变性 1-4 。WRN 的消耗会在 MSI 细胞中诱导广泛的 DNA 双链断裂，从而导致细胞周期停滞和/或细胞凋亡。然而，WRN 保护 MSI 相关癌症免受双链断裂的机制仍不清楚。在这里，我们显示 TA-二核苷酸重复在 MSI 细胞中高度不稳定，并经历大规模扩张，这与先前描述的几个核苷酸 5 的插入或缺失突变不同。扩展的 TA 重复形成非 B DNA 二级结构，这些结构会阻止复制叉，激活 ATR 检查点激酶，并需要 WRN 解旋酶解旋。在没有 WRN 的情况下，扩展的 TA-二核苷酸重复序列容易被 MUS81 核酸酶切割，导致大量染色体破碎。这些发现确定了一种独特的生物标志物，它是对 WRN 的合成致死依赖的基础，并支持开发针对 MSI 相关癌症的 WRN 的治疗剂。在具有微卫星不稳定性的细胞中，扩展的 TA-二核苷酸重复形成十字形结构，在没有 WRN 解旋酶的情况下会停止复制叉并导致染色体破碎。