Wrap53-1α and Wrap53-1β exert distinct p53-dependent effects on radiosensitivity in lung adenocarcinoma

This study elucidates the distinct roles of Wrap53 isoforms (1α/1β) in lung adenocarcinoma (LUAD) radiosensitivity through integrated bioinformatics and functional analyses. Bioinformatics revealed Wrap53-associated enrichment in DNA repair and p53 pathways, with TCGA data linking its expression to prognosis and chemotherapy response. Functional studies demonstrated isoform- and p53 context-dependent effects: In p53-wild type A549 cells, Wrap53-1α silencing upregulated p53, enhanced radiosensitivity through Bax/Bcl-2-mediated apoptosis, and impaired DNA repair through RAD51 recombinase (RAD51)/Breast cancer susceptibility gene 1 (BRCA1) regulation. Conversely, in p53-mutant H1975 cells, silencing either Wrap53-1α or Wrap53-1β individually increased colony formation. Wrap53-1α was found to modulate post-radiation G2/M arrest through cyclin-dependent kinase 1 (CDK1) regulation, with effects contingent on p53 status. Importantly, Wrap53 expression correlated with differential chemosensitivity. High Wrap53 tumors showed increased cisplatin sensitivity but resistance to docetaxel, while low-expressing tumors were resistant to paclitaxel and vinca alkaloids. Our findings reveal a previously unappreciated inverse correlation between Wrap53-1α and p53 in LUAD cells and establish a molecular network where Wrap53 isoforms and p53 status collectively determine LUAD radiosensitivity.