Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Nature. 2020 Oct;586(7828):292-298. doi: 10.1038/s41586-020-2769-8. Epub 2020 Sep 30.
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. 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. 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.
RecQ DNA 解旋酶 WRN 是具有微卫星不稳定（MSI）的癌细胞的合成致死靶点，这是一种由错配修复受损引起的遗传高突变形式。WRN 的耗竭会在 MSI 细胞中诱导广泛的 DNA 双链断裂，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尚不清楚。在这里，我们表明 TA-二核苷酸重复在 MSI 细胞中高度不稳定，并发生大规模扩展，与先前描述的少数核苷酸的插入或缺失突变明显不同。扩展的 TA 重复形成非 B DNA 二级结构，可使复制叉停滞，激活 ATR 检查点激酶，并需要 WRN 解旋酶进行解旋。在没有 WRN 的情况下，扩展的 TA-二核苷酸重复易被 MUS81 核酸内切酶切割，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，该标志物是对 WRN 的合成致死依赖性的基础，并支持开发针对 MSI 相关癌症的靶向 WRN 的治疗药物。
