αKG-mediated carnitine synthesis drives DNA repair via histone acetylation
- Nature. 2026 May 27:10.1038/s41586-026-10584-7. doi: 10.1038/s41586-026-10584-7.
- 1. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
- 2. Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- 3. Tsinghua University, Beijing, China.
- 4. Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
- 5. Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
- 6. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
- 7. Department of Radiation Oncology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- 8. Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA.
- 9. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- 10. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
- 11. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA.
- 12. Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
- 13. Biostatistics Facility, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
- 14. Department of Medicine, Division of Hematology/Oncology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- 15. Department of Computational & Systems Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- 16. Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
- 17. Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. [email protected].
- 18. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA. [email protected].
- 19. Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
Homologous recombination (HR) deficiency increases sensitivity to DNA-damaging agents that are commonly used to treat Cancer1. In HR-proficient cancers, the metabolic mechanisms that drive response or resistance to DNA-damaging agents remain unclear. Here we have identified that depletion of α-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA-damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases2 (αKGDDs), and previous work has focused almost exclusively on the demethylase functions of αKGDD. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that trimethyllysine hydroxylase epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for the survival of HR-proficient cells in the presence of DNA-damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation and was non-redundant with Other nucleo-cytosolic acetyl-CoA-generating pathways. The increase in histone acetylation by means of the αKG-carnitine axis promoted HR-mediated DNA repair through site-specific histone acetylation. Finally, we observed a positive correlation between TMLHE and histone acetylation in patient samples and found that high TMLHE or acetylcarnitine correlates with worse progression-free survival in patients treated with DNA-damaging agents. This study demonstrates for the first time, to our knowledge, that αKG affects site-specific histone acetylation and provides a mechanism of HR proficiency through carnitine synthesis. Moreover, these data provide a metabolic avenue for inducing HR deficiency and promoting sensitivity to DNA-damaging agents.
-
Cat. No.Product NameDescriptionTargetResearch Area
-
target: Isocitrate Dehydrogenase (IDH)Research Areas: Cancer