Programmed DNA double strand breaks fuel chromatin remodeling and potentiate stimulus-dependent gene induction

Strikingly, repeated rounds of DSB formation do not diminish but instead potentiate transcriptional output. Over time, the promoter’s cis interactions become more refined and “pruned,” coinciding with increased trans contacts, and these architectural changes persist long after the breaks have been repaired. Notably, even when DSB repair fidelity is low, ERG induction remains robust, underscoring a remarkable resilience in promoter function.

Together, our findings reveal a novel model of transcriptional regulation in which transient DSBs act as powerful catalysts for dynamic and progressively fine-tuned 3D genome reorganization. This work broadens our understanding of how cells leverage controlled DNA breaks to support rapid transcriptional responses, while also facilitating adapted future responses.