YTHDF3 facilitates DNA damage response by recognizing METTL3-mediated m6A modification to promote chemotherapy resistance in glioblastoma

作者：Meng Cheng, Ying Pang, Rui Wang, Xu Chen, Chunyu Zhang, Chunyu Zhang, Yuntong Yang, Tongjie Ji, Yueyao Wu, Jingzhe Wang, Siyi Xu, Zhigang Wang, Min Liu, Chunlong Zhong, Chunlong Zhong · 发表于：Cancer Letters · 年份：2026 · DOI：10.1016/j.canlet.2026.218445 · 被引用次数：2 · 研究领域：RNA modifications and cancer、Metalloenzymes and iron-sulfur proteins、Ubiquitin and proteasome pathways

Glioblastoma (GBM) poses a formidable challenge in the field of oncology because of its pronounced resistance to traditional therapeutic approaches. N6-methyladenosine (m 6 A) modification is a prevalent posttranscriptional modification that significantly influences cellular processes by modulating gene expression. However, the role of m 6 A in the regulation of the DNA damage response (DDR) in GBM cells remains unclear. Through integrated bioinformatics and functional studies, we identified the m 6 A reader YTHDF3 as a central regulator of the DDR in GBM, and the elevated expression levels of YTHDF3 were correlated with unfavorable clinical outcomes in GBM patients. Human GBM cell lines and patient-derived GBM cells (PDC) models were used to explore the biological function of YTHDF3. Following treatment with temozolomide (TMZ), the level of m 6 A modification was increased, facilitating YTHDF3-mediated DNA damage repair. The knockdown of METTL3 resulted in a reduction in functional m 6 A modification and suppressed the expression of DDR core factors, which are mediated by YTHDF3. Mechanistically, YTHDF3 recognizes the m 6 A binding site of DNA damage response genes (BRCA1, RAD51, RIF1 and 53BP1) and promotes their translation through m 6 A methylation, thereby initiating homologous recombination (HR) and nonhomologous end joining (NHEJ) repair to resist endogenous and exogenous DNA damage. Consequently, our study elucidates the crucial role of YTHDF3 in GBM and provides valu...