{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nReplication protein A3 (RPA3) is a critical subunit of the heterotrimeric replication protein A complex, which is central to numerous aspects of DNA metabolism such as replication, recombination, repair, and telomere maintenance. Although early studies suggested that RPA3 act merely as a structural adaptor within the complex, recent work has revealed that it directly interacts with single‐stranded DNA on the 3′ side, and its modular organization enables dynamic binding and regulated handoff of ssDNA during downstream processing events. This evolving understanding positions RPA3 as an active participant in coordinating DNA transactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in safeguarding and processing ssDNA, RPA3 contributes to DNA repair and chromatin regulation. For instance, RPA3 partners with the histone chaperone HIRA to form RPA–HIRA–H3.3 complexes that facilitate the deposition of newly synthesized histone variant H3.3 at promoters and enhancers, thereby influencing gene transcription. Furthermore, genetic studies exploring polymorphisms in DNA repair pathways have implicated RPA3 as a candidate gene associated with cancer susceptibility, while its evaluation in candidate gene screens for autosomal recessive nonsyndromic hearing impairment underscored its potential as a marker of genomic integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulated RPA3 expression has emerged as an important factor in cancer progression and therapeutic responses. In hepatocellular carcinoma, suppression of RPA3 by miR-146a-5p modulates the DNA damage repair pathway, enhancing radiosensitivity. In nasopharyngeal carcinoma, overexpression of RPA3 increases radioresistance by promoting efficient DNA repair and enhanced RAD51 foci formation. Aberrant RPA3 levels have also been linked to oncogenic signaling in multiple tumor types: in lung adenocarcinoma and gliomas, elevated RPA3 activates AKT/mTOR and PI3K-AKT-mTOR pathways, respectively, thereby promoting cell proliferation, invasiveness, and poorer patient outcomes. Furthermore, its inclusion in multi-gene prognostic signatures in breast cancer and investigations in bladder urothelial carcinoma underscore its potential utility as a biomarker in the clinical setting, while genetic variation in RPA3 has been associated with altered glioma risk."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zhongming Dai, Shufang Wang, Weiping Zhang, et al. 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