Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability. The telomeric repeat-containing RNA (TERRA) that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop. In tumor cells, R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres (ALT) pathway. Dysregulated R-loops can cause stalled replication forks and telomere instability. However, how R-loops are recognized and regulated, particularly at telomeres, is not well understood. We discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination. Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses (DDR). In addition, ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway. Using the proximity-dependent biotin identification (BioID) technology, we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases, including DHX9. Importantly, ILF3 may aid in the resolution of telomeric R-loops through its interaction with DHX9. Our findings suggest that ILF3 may function as a reader of telomeric R-loops, helping to prevent abnormal homologous recombination and maintain telomere homeostasis.

中文翻译：

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ILF3 作为端粒 R 环解读器，保​​护端粒免遭异常同源重组。

端粒是线性染色体末端的特殊结构，可保护基因组稳定性。从亚端粒区域转录的含有端粒重复的RNA (TERRA)可以侵入双链DNA区域并形成称为R环的RNA:DNA杂合结构。在肿瘤细胞中，R 环的形成与基因表达和端粒选择性延长 (ALT) 途径密切相关。R 环失调会导致复制叉停滞和端粒不稳定。然而，R 环如何被识别和调节，特别是在端粒处，尚不清楚。我们发现ILF3选择性地与端粒R环结合并保护端粒免遭异常同源重组。敲除 ILF3 会导致端粒处出现过多的 R 环，并触发端粒 DNA 损伤反应 (DDR)。此外，ILF3 缺乏会破坏端粒稳态并导致 ALT 通路异常。利用邻近依赖性生物素识别（BioID）技术，我们绘制了 ILF3 相互作用组图谱，发现 ILF3 可以与多种 DNA/RNA 解旋酶（包括 DHX9）相互作用。重要的是，ILF3 可能通过与 DHX9 的相互作用有助于端粒 R 环的解析。我们的研究结果表明，ILF3 可能充当端粒 R 环的读取器，有助于防止异常同源重组并维持端粒稳态。