RPA1 is the largest subunit of the replication protein A (RPA) complex, a single-stranded DNA-binding protein essential for DNA replication and damage response 1. As part of the heterotrimeric RPA complex, RPA1 binds and stabilizes single-stranded DNA intermediates formed during replication or DNA stress, preventing reannealing while recruiting proteins involved in DNA metabolism 2. RPA1 plays critical roles in homologous recombination repair by recruiting RAD51 and facilitating DNA end resection, and in nucleotide excision repair through XPA/XPG recruitment 2. The protein also regulates ATR kinase activation via ATRIP recruitment, controlling DNA damage checkpoint responses 3. RPA1 maintains adequate nuclear RPA pools to prevent replication catastrophe when ATR suppresses unscheduled origin firing 3. Additionally, RPA1 participates in telomere maintenance 1. Post-translational modifications regulate RPA1 function: lactylation enhances single-stranded DNA and MRN complex binding to promote homologous recombination 4, while ubiquitination by RNF213 inhibits HR repair 5. RPA1 deficiency confers hypersensitivity to PARP inhibitors, demonstrating synthetic lethality relevant to cancer therapy 6. Germline RPA1 gain-of-function mutations cause telomere biology disorders with bone marrow failure and pulmonary fibrosis, while enrichment of damaging variants occurs in pediatric cancers 17.