Transketolase attenuates the chemotherapy sensitivity of glioma cells by modulating R-loop formation
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.
Authors
- Youjun Chu
- Feng Yuan (ORCID: https://orcid.org/0000-0002-8132-9224)
- Huaichao Zhang
- Jinsen Zhang (ORCID: https://orcid.org/0000-0003-1564-053X)
- Yonghe Wu (ORCID: https://orcid.org/0000-0001-9667-8198)
- Tianping Peng
- Hao Xu (ORCID: https://orcid.org/0000-0001-6499-8701)
- Wei Hua (ORCID: https://orcid.org/0000-0001-6409-5078)
- Minjie Fu (ORCID: https://orcid.org/0000-0003-4145-5450)
- Licheng Zhang (ORCID: https://orcid.org/0000-0002-1024-4098)
- Chao Gao (ORCID: https://orcid.org/0000-0002-9200-6164)
- Mengli Zhang (ORCID: https://orcid.org/0000-0003-3497-6266)
- Dan Ye (ORCID: https://orcid.org/0000-0002-6306-4808)
- Pu Wang (ORCID: https://orcid.org/0000-0002-7555-0512)
- Ying Mao (ORCID: https://orcid.org/0000-0001-8055-115X)
Institutions
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- ShanghaiTech University (CN)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
- Shanghai Clinical Research Center (CN)
- Huashan Hospital (CN)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.115142
- Citations
- 7
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 6.55
Funders
- National Natural Science Foundation of China
- Chinese Academy of Meteorological Sciences
- National Key Research and Development Program of China