Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs

Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism activated in similar to 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.

Automated summary

This study found that telomeric dilncRNAs are significantly elevated in ALT cells, and inhibition of teloC dilncRNAs leads to DNA replication stress responses, increased genomic instability, and selective induction of apoptosis in ALT cells. These results reveal the essential role of teloC dilncRNA in coordinating the recruitment of DDR factors to ALT telomeres and the survival of ALT cancer cells.