ZNF512B protects critical regulatory regions to safeguard long term genomic integrity. [CUT&RUN]

Active regions in the genome are more prone to DNA damage (Schwer et al., 2016), but the mutations occur less often in these regions (Martincorena et al., 2012; Monroe et al., 2022; Xia et al., 2020; Zhang and Yang, 2015), indicating involvement of unknown protective machinery. Chronic DNA damage signaling induces senescence associated secretory phenotype (SASP), which mediates pathophysiological functions of senescent cells during aging (Herranz and Gil, 2018), however, the molecular players governing SASP remain poorly understood. Here we performed a genome wide CRISPR screening by implementing a SASP specific reporter system and a guide RNA library targeting regulatory regions and identify several novel SASP repressors. ZNF512B is one such factor that prioritizes DNA repair around regulatory regions associated with highly expressed genes. ZNF512B selectively recruits NuRD nucleosome remodeling complexes to damage loci and ensure faithful timely manner repair. ZNF512B depletion induces SASP, and its overexpression inhibits SASP in various in vitro and in vivo models by modulating DNA repair. ZNF512B overexpression slows down cutaneous wound healing and reduces damage associated with acute liver injury by repression of SASP. ZNF512B is a known prognostic factor for amyotrophic lateral sclerosis (ALS) (Jiang et al., 2021; Tetsuka et al., 2013; Yang et al., 2015; Yu et al., 2018) and its ablation in human neuromuscular organoids leads to depletion of astroglia compartment, a possible mechanism leading to subsequent defects in neuromuscular pathology in ALS. Taken together these findings have important implications for our understanding of repair bias around functionally constrained regions to safeguard long term genome integrity during aging and age associated pathology.