端粒选择性延长 (ALT) 是一种端粒维持机制，在约 10-15% 的癌症中被激活，其特征是端粒损伤。端粒损伤诱导的长非编码 RNA (dilncRNA) 在功能失调的端粒处转录，有助于端粒 DNA 损伤反应 (DDR) 的激活和修复。在这里，我们观察到端粒 dilncRNA 在 ALT 细胞中优先升高。用反义寡核苷酸抑制富含 C (teloC) 的 dilncRNA 会导致 ALT 细胞中 DNA 复制应激反应、基因组不稳定性增加和选择性诱导凋亡。细胞死亡依赖于 DNA 复制，并且会因 DNA 复制压力而增加。从机制上讲，teloC dilncRNA 抑制可减少 RAD51 和 53BP1 向端粒的募集，增强 BIR 机制的参与，并增加 C 环和端粒姐妹染色单体交换，而不增加端粒非 S 期合成。这些结果表明，teloC dilncRNA 对于将 DDR 因子协调招募到 ALT 端粒是必要的，并且对于 ALT 癌细胞的生存至关重要。© 2023。作者。

Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism activated in ~10-15% of cancers, characterized by telomeric damage. Telomeric damage-induced long non-coding RNAs (dilncRNAs) are transcribed at dysfunctional telomeres and contribute to telomeric DNA damage response (DDR) activation and repair. Here we observed that telomeric dilncRNAs are preferentially elevated in ALT cells. Inhibition of C-rich (teloC) dilncRNAs with antisense oligonucleotides leads to DNA replication stress responses, increased genomic instability, and apoptosis induction selectively in ALT cells. Cell death is dependent on DNA replication and is increased by DNA replication stress. Mechanistically, teloC dilncRNA inhibition reduces RAD51 and 53BP1 recruitment to telomeres, boosts the engagement of BIR machinery, and increases C-circles and telomeric sister chromatid exchanges, without increasing telomeric non-S phase synthesis. These results indicate that teloC dilncRNA is necessary for a coordinated recruitment of DDR factors to ALT telomeres and it is essential for ALT cancer cells survival.© 2023. The Author(s).