GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE297nnn/GSE297164/suppl/GSE297164_radID_vs_Mock.deseq2.txt.gzftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE297nnn/GSE297164/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE297164GEOGSEfalseRNA-seq profiling of radioiodine-treated differentiated thyroid cancer cells reveals DDR pathway regulation during iodine toleranceAim: To investigate the role of ataxia-telangiectasia mutated (ATM) in thyroid cancer (TC) progression and radioactive iodine (RAI) resistance, exploring its potential as a therapeutic target. Methods: Single-cell RNA sequencing of 28 TC tumors / normal tissues traced ATM dynamics during dedifferentiation. Clinical validation used tissue microarrays (TMAs) on 89 RAI resistance (RAIR) and RAI-avid differentiated thyroid cancer (DTC) specimens. Preclinical models evaluated the synergy between the ATM inhibitor AZD1390 and RAI. Mechanistic studies employed RNA-seq, comet assays, cell cycle analysis, and AP site quantification. Results: scRNA-seq revealed progressive ATM upregulation during malignant progression, correlating with cell cycle dysregulation. TMAs confirmed elevated ATM expression in anaplastic thyroid cancer (ATC) vs. papillary thyroid cancer, PTC and RAIR tumors. In vivo, AZD1390 + 131I synergistically suppressed tumor growth and enhanced apoptosis. RAI predominantly induced apurinic/apyrimidinic (AP) sites rather than double-strand breaks (DSBs). ATM inhibition disrupted base excision repair (BER) coordination and G2/M checkpoint control, forcing cells with unresolved AP sites into mitotic catastrophe. Conclusion: ATM mediates RAIR in thyroid cancer by promoting AP site repair and inducing cell cycle arrest. Inhibiting ATM converts repairable damage into lethal DNA lesions, restoring RAI sensitivity, suggesting ATM as a therapeutic target for RAI-refractory thyroid cancer.2026/06/18GSE297164GSM8984874GSM8984873GSM8984872GSM8984871GSM8984870GSM8984869GSM8984876GSM89848759052297164Homo sapiens[42046098]