RPA3 is the smallest subunit of the heterotrimeric replication protein A (RPA) complex, which binds and stabilizes single-stranded DNA during DNA replication and stress responses 1. As part of canonical RPA, it recruits repair factors including RAD51 and RAD52 for double-strand break repair, and XPA/XPG for nucleotide excision repair 2. RPA3 possesses direct ssDNA-binding activity, potentially determining complex polarity on DNA 1. It also functions within an alternative RPA complex (aRPA) containing RPA4, which antagonistically regulates CAG repeat expansions in neurodegenerative diseases—while canonical RPA suppresses expansions and rescues motor phenotypes in SCA1 models, aRPA promotes expansions 3. Clinically, RPA3 dysregulation associates with multiple malignancies. High RPA3 expression in gliomas correlates with poor prognosis through PI3K-AKT-mTOR pathway activation, promoting proliferation and invasion 4. In nasopharyngeal carcinoma, elevated RPA3 enhances radioresistance via increased DNA repair and RAD51 foci formation, predicting poor survival 5. Genetic variants in RPA3 show protective associations against glioma susceptibility in Chinese populations 6, and RPA3 variants appear enriched in pediatric cancer cohorts 7. Additionally, RPA3 variants associate with rheumatoid arthritis-interstitial lung disease risk 8, suggesting broader inflammatory implications.