Fig. 1: D-2-HG compromises HR DNA repair via inhibition of TET1/2.

a γH2A.X foci number. U251 cells were treated with DMSO, 150 μM TMZ or 150 μM BCNU for 24 h. Group differences were tested with one-way ANOVA. **p < 0.01. All p < 0.0001; data are mean ± SEM from three independent experiments. b–e Activation of DDR. IDH1^WT, IDH1^R132H U251 or U251 cells were treated with 150 μM TMZ ± 5 μM AG-120 (b); 150 μM TMZ/150 μM BCNU, 0.5 mM D-2-HG, 1 mM αKG (+), 10 mM αKG (++) for 24 h (c–e). f, g Comet assay. f U251 were treated with 150 μM TMZ, 0.5 mM D-2-HG, 10 mM αKG for 24 h. **p < 0.01. All the indicated p < 0.0001; g U251 with TET1/TET2 knockout were treated with DMSO or 150 μM TMZ for 24 h. **p < 0.01. All the indicated p < 0.0001; group differences were tested with one-way ANOVA. Data are mean ± SEM from three independent experiments. h, i Western blotting. U251 with control sgRNA, TET1/TET2 knockout, TET1/TET2 knockout with TET1 or TET2 overexpression were treated with 150 μM TMZ for 24 h. j Flow cytometry analysis. DD-Sce-I-GR DRGFP U2OS were treated with 0.5 μM Shield1 and 0.2 mM TA, 0.5 mM D-2-HG, 10 mM αKG, TET1 or TET2 overexpression for 24 h. k Quantification for (j). *p < 0.05, **p < 0.01. D-2-HG vs D-2-HG + 1 μg TET1, p = 0.01. Other p < 0.0001. Group differences were tested with one-way ANOVA. Data are mean ± SEM from three independent experiments. l Activation of DDR. U251 IDH1^WT/IDH1^R132H with TET1 or TET2 overexpression were treated with 150 μM TMZ. m, n γH2A.X foci number. U251 with TET1/TET2 knockout, TET1/TET2 overexpression was treated with 150 μM TMZ for 24 h. *p < 0.05, **p < 0.01. TET2 KO+ vs TET2 OE, p = 0.0393. All other p < 0.0001. Group differences were tested with one-way ANOVA. Data are mean ± SEM from three independent experiments. Source Data are provided as a Source Data file.