ZNF512B protects critical regulatory regions to safeguard long term genomic integrity. [scRNA-Seq]

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 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 ALS-associated pathology.