ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.

Abstract

Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.