Malignant cells ensure telomere maintenance by the alternative lengthening of telomeres (ALT) in the absence of telomerase activity (TA). The retrotransposons "long interspersed nuclear element-1" (LINE-1, L1) are expressed in malignant cells and are primarily known to contribute to complex karyotypes. Here we demonstrate that LINE-1 ribonucleoprotein particles (L1-RNPs) expression is significantly higher in ALT+- versus in TA+-human glioma. Analyzing a role of L1-RNP in ALT, we show that L1-RNPs bind to telomeric repeat containing RNA (TERRA), which is critical for telomere stabilization and which is overexpressed in ALT+ cells. In turn, L1-RNP knockdown (KD) abrogated the nuclear retention of TERRA, resulted in increased telomeric DNA damage, decreased cell growth and reduced expression of ALT characteristics such as c-circles and PML-bodies. L1-RNP KD also decreased the expression of Shelterin- and the ALT-regulating protein Topoisomerase IIIα (TopoIIIα) indicating a more general role of L1-RNPs in supporting telomeric integrity in ALT. Our findings suggest an impact of L1-RNP on telomere stability in ALT+ dependent tumor cells. As L1-RNPs are rarely expressed in normal adult human tissue those elements might serve as a novel target for tumor ablative therapy.

中文翻译：

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较长的散布的element-1核糖核蛋白颗粒在端粒依赖性细胞的替代性延长中保护端粒末端。

恶性细胞通过在没有端粒酶活性（TA）的情况下通过延长端粒（ALT）来确保端粒的维持。逆转座子“长散布的核素-1”（LINE-1，L1）在恶性细胞中表达，主要已知其有助于复杂的核型。在这里，我们证明LINE-1核糖蛋白颗粒（L1-RNPs）的表达在ALT +-中比在TA +-人神经胶质瘤中明显更高。分析L1-RNP在ALT中的作用，我们表明L1-RNPs结合含有端粒重复序列的RNA（TERRA），这对于端粒稳定至关重要，并且在ALT +细胞中过表达。反过来，L1-RNP敲除（KD）消除了TERRA的核保留，导致端粒DNA损伤增加，降低细胞生长并降低ALT特性（例如c环和PML抗体）的表达。L1-RNP KD还降低了Shelterin-和ALT调节蛋白拓扑异构酶IIIα（TopoIIIα）的表达，表明L1-RNP在支持ALT端粒完整性方面具有更普遍的作用。我们的发现表明，L1-RNP对ALT +依赖性肿瘤细胞中端粒的稳定性有影响。由于L1-RNP在正常成人组织中很少表达，因此这些元素可能成为肿瘤消融治疗的新靶标。