Finely-tuned regulator of DNA repair: FBXW7-185aa may modulate glioblastoma radiosensitization and the tumor immune microenvironment

• FBXW7–185aa is recruited to DNA damage sites in an ATM-dependent manner. • FBXW7–185aa modulates non-homologous end joining repair efficiency in glioblastoma cells. • FBXW7–185aa influences cellular radiosensitivity through regulation of DNA repair. • FBXW7–185aa, by fine-tuning NHEJ, may serve as a molecular switch influencing the immunogenicity of radiotherapy in glioblastoma. • circ-FBXW7 encodes a functional protein involved in the DNA damage response. DNA double-strand breaks (DSBs) are among the most severe forms of DNA damage, and their cellular consequences depend on the efficiency of DNA repair pathways. Non-homologous end joining (NHEJ) provides a rapid mechanism to reconnect broken DNA strands and is a major pathway for maintaining genomic stability. FBXW7α is the substrate-selective unit within the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, imparting specificity by recruiting proteins destined for ubiquitin-mediated turnover. It has recently been reported to mediate XRCC4 ubiquitylation during DNA damage, and is a recognized tumor suppressor, thereby promoting NHEJ. A circular RNA derived from FBXW7 gene exons 3 and 4 (circ-FBXW7) has been identified. This circRNA encodes a 185-amino acid protein, named FBXW7-185aa, which contains a spanning-junction open reading frame (ORF). We found that compared with FBXW7α, FBXW7-185aa was recruited more slowly to DNA damage sites in glioblastoma (GBM) cells. Functionally, FBXW7-185aa may enhance NHEJ repair by facilitating the removal of FBXW7α from DNA damage lesions, thereby promoting the subsequent steps of DNA repair. Efficient DNA repair can enable tumor cells to survive genotoxic stressors like radiotherapy. Radiotherapy is also known to modulate the tumor immune microenvironment. Therefore, our findings suggest that FBXW7-185aa may represent a potential molecular nexus between DNA damage response and tumor–immune interactions. Moreover, depletion of FBXW7–185aa was associated with increased sensitivity of GBM cells to pevonedistat, a drug that inhibits the ubiquitin-like modification of the protein NEDD8, when combined with radiation. Together, our results indicate that FBXW7-185aa acts as a fine-tuning regulator of NHEJ through its interaction with FBXW7α, adding a new layer to the complexity of FBXW7 gene-derived proteins in DNA repair. These findings provide a mechanistic basis for exploring how fine-tuned DNA repair dynamics may influence GBM radiosensitivity and potentially impact tumor immunogenicity, although direct immunological effects remain to be determined.