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

Minjie Fu; Mengli Zhang; Licheng Zhang; Yuan Feng; Chao Gao; Hao Xu; Jinsen Zhang; Huaichao Zhang; Tianping Peng; Youjun Chu; Yonghe Wu; Pu Wang; Dan Ye; Ying Mao; Wei Hua

doi:10.1016/j.celrep.2024.115142

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

Cell Rep. 2025 Jan 9;44(1):115142. doi: 10.1016/j.celrep.2024.115142. Online ahead of print.

Authors

Minjie Fu¹, Mengli Zhang¹, Licheng Zhang¹, Yuan Feng¹, Chao Gao², Hao Xu¹, Jinsen Zhang¹, Huaichao Zhang¹, Tianping Peng³, Youjun Chu³, Yonghe Wu³, Pu Wang², Dan Ye⁴, Ying Mao⁵, Wei Hua⁶

Affiliations

¹ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China.
² Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
³ Shanghai Institute for Advanced Immunochemical Studies (SIAIS), Shanghai Tech University, Shanghai 201210, China.
⁴ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. Electronic address: [email protected].
⁵ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China. Electronic address: [email protected].
⁶ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China. Electronic address: [email protected].

PMID: 39792560
DOI: 10.1016/j.celrep.2024.115142

Abstract

Glioblastoma (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.

Keywords: CP: Cancer; R-loops; TKT; chemotherapy sensitivity; glioma.