The ribonuclease DIS3 is one of the most frequently mutated genes in the hematological cancer multiple myeloma, yet the basis of its tumor suppressor function in this disease remains unclear. Herein, exploiting the TCGA dataset, we found that DIS3 plays a prominent role in the DNA damage response. DIS3 inactivation causes genomic instability by increasing mutational load, and a pervasive accumulation of DNA:RNA hybrids that induces genomic DNA double-strand breaks (DSBs). DNA:RNA hybrid accumulation also prevents binding of the homologous recombination (HR) machinery to double-strand breaks, hampering DSB repair. DIS3-inactivated cells become sensitive to PARP inhibitors, suggestive of a defect in homologous recombination repair. Accordingly, multiple myeloma patient cells mutated for DIS3 harbor an increased mutational burden and a pervasive overexpression of pro-inflammatory interferon, correlating with the accumulation of DNA:RNA hybrids. We propose DIS3 loss in myeloma to be a driving force for tumorigenesis via DNA:RNA hybrid-dependent enhanced genome instability and increased mutational rate. At the same time, DIS3 loss represents a liability that might be therapeutically exploited in patients whose cancer cells harbor DIS3 mutations.

中文翻译：

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核糖核酸酶 DIS3 的缺失通过破坏 DNA:RNA 杂交代谢阻碍了骨髓瘤的基因组完整性

核糖核酸酶DIS3是血液癌症多发性骨髓瘤中最常突变的基因之一，但其在该疾病中的肿瘤抑制功能的基础仍不清楚。在此，利用 TCGA 数据集，我们发现 DIS3 在 DNA 损伤反应中起着重要作用。DIS3 失活通过增加突变负荷和 DNA:RNA 杂合体的普遍积累导致基因组不稳定，从而诱导基因组 DNA 双链断裂 (DSB)。DNA:RNA 杂交积累还阻止了同源重组 (HR) 机制与双链断裂的结合，从而阻碍了 DSB 修复。DIS3 失活细胞对 PARP 抑制剂变得敏感，这表明同源重组修复存在缺陷。因此，多发性骨髓瘤患者细胞发生DIS3突变具有增加的突变负担和促炎干扰素的普遍过度表达，与 DNA：RNA 杂合体的积累相关。我们提出骨髓瘤中的DIS3缺失是通过 DNA:RNA 杂交依赖性增强的基因组不稳定性和增加的突变率促进肿瘤发生的驱动力。同时，DIS3丢失代表了一种可能在癌细胞携带DIS3突变的患者中被用于治疗的责任。