Transketolase attenuates the chemotherapy sensitivity of glioma cells by modulating R-loop formation

Highlights•TKT attenuates the chemosensitivity in glioma independent of catalytic activity•Chemotherapeutic drugs promote TKT's nuclear translocation in glioma cells•TKT interacts with XRN2 to regulate the resolution and removal of R-loopsSummaryGlioblastoma (GBM) is a highly lethal malignant brain tumor with poor survival rates, and chemoresistance poses a significant challenge to the treatment of patients with GBM. Here, we show that transketolase (TKT), a metabolic enzyme in the pentose phosphate pathway (PPP), attenuates the chemotherapy sensitivity of glioma cells in a manner independent of catalytic activity. Mechanistically, chemotherapeutic drugs can facilitate the translocation of TKT protein from the cytosol into the nucleus, where TKT physically interacts with XRN2 to regulate the resolution and removal of R-loops. Depletion of TKT leads to increased R-loop accumulation and genome instability, increasing the susceptibility of glioma cells to chemotherapy. In conclusion, our study reveals a non-metabolic function of TKT in regulating R-loop dynamics, genome instability, and chemotherapy sensitivity in gliomas.Graphical abstract