ADPRS encodes ARH3 (ADP-ribosylhydrolase 3), a critical enzyme that regulates cellular ADP-ribosylation by hydrolyzing ADP-ribose modifications from proteins and free poly(ADP-ribose) chains 1. ARH3 functions as the primary serine mono-ADP-ribosylhydrolase, specifically removing mono-ADP-ribose attached to serine residues on proteins, which constitutes the predominant form of protein ADP-ribosylation during DNA damage responses 1. The enzyme also degrades free poly(ADP-ribose) chains synthesized in response to DNA damage, protecting cells from poly(ADP-ribose)-dependent cell death (parthanatos) 2. ARH3 localizes to the nucleus, cytoplasm, and mitochondria, where it maintains cellular homeostasis by regulating ADP-ribosylation levels 1. Loss-of-function mutations in ADPRS cause childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS), characterized by developmental delay, seizures, progressive muscle weakness, and respiratory failure 3. The ARH3H182R variant disrupts protein stability and nuclear localization, leading to accumulation of mono-ADP-ribosylated species 3. ARH3 deficiency creates synthetic lethality with PARG and can confer PARP inhibitor resistance, highlighting its therapeutic relevance in cancer treatment 1.