DROSHA, DICER, and damage-induced long ncRNA control BMI1-dependent transcriptional repression at DNA double-strand break

The activation of the DNA-damage response (DDR) enforces the transcriptional silencing of genes near DNA double-strand breaks (DSBs), a process called DSB-induced silencing in cis (DISC). DISC involves the kinase ATM and the polycomb repressive complex 1 (PRC1) component BMI1. Conversely, DSBs also trigger transcription of damage-induced long non-coding RNAs (dilncRNAs) in an MRE11-RAD50-NBS1 (MRN)-complex-dependent manner. MRN recruits the ribonuclease DROSHA, which, along with DICER, enhances DDR signaling and repair. We show that dilncRNAs, DROSHA, and DICER regulate DISC. MRN or ATM inhibition disrupts DISC, while enoxacin, a DICER activator, restores it even without ATM activity. Mechanistically, DROSHA and DICER enable BMI1 recruitment and H2A-K119 ubiquitination at DSBs. BMI1 interacts with DROSHA and dilncRNAs in a DICER-dependent manner. Blocking dilncRNAs by antisense oligonucleotide and Cas13 reduces BMI1 recruitment and DISC. We propose that DROSHA, DICER, and dilncRNAs mediate DISC by promoting PRC1 recruitment and chromatin modification at DSBs.