Identification of a DNA Damage Response-Related Prognostic Signature and Functional Validation of SMC3 in Glioma

DNA damage response (DDR) deficiencies are linked to tumorigenesis and progression. However, the association of DDR with prognosis and therapeutic response in glioma has not been fully illustrated. TCGA and CGGA databases were used to acquire RNA-seq and clinical data about gliomas. LASSO-Cox regression was introduced to establish a DDR-based risk signature. The single-sample gene set enrichment analysis (ssGSEA) algorithm was used to estimate immune infiltrates. The performance of the signature and nomogram in predicting survival was evaluated using ROC curves. Connectivity Map (CMap) analysis was used to nominate candidate compounds, and pRRophetic was used to predict drug sensitivity. Through LASSO-Cox regression, we developed a prognostic risk score based on five DDR-related genes (GADD45G, HDAC1, RRM2, SMC3, and WEE1). Higher risk scores were associated with shorter overall survival and remained significant in multivariable Cox analyses. A prognostic nomogram achieved 1-, 3-, and 5-year AUCs of 0.901, 0.936, and 0.903 in TCGA and 0.776, 0.816, and 0.802 in CGGA, respectively. High-risk tumors showed enrichment of TNFα signaling via NFκB and IL6/JAK/STAT3 gene sets, together with differences in inferred immune cell-associated features and immune checkpoint gene expression. Computational drug sensitivity analyses associated higher risk scores with lower predicted IC50 values for GSK269962A, pazopanib, rapamycin, and NVP-BEZ235, providing hypotheses for subsequent experimental validation. SMC3 overexpression inhibited glioma cell proliferation and migration in vitro. The DDR-related signature showed prognostic value and associations with immune-related transcriptional features in glioma, with in vitro evidence suggesting a functional role for SMC3.