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.
Apoorva Uboveja  1  2 Baixue Yang  1  2  3 Raquel Buj  1  2 Amandine Amalric  1  2  4 Hui Wang  2 Naveen Kumar Tangudu  2 Aidan R Cole  1  2 Julie A Disharoon  5 Richard S Fang  2 Evan Levasseur  2 Miho Naruse  1  2 Zhentai Huang  2 Emily Megill  4 Daniel S Kantner  4 Adam Chatoff  4 Hafsah Ahmad  4 Mariola M Marcinkiewicz  4 Sarah Graff  6 Ellen De Pieri  6 Andrea Andress Huacachino  4 Frank P Vendetti  7 Jeff Danielson  2 Erika S Dahl  8 Jennifer L Pennise  4 Esther Elishaev  9 Alison Jaccard  4  10 Lauren Borho  11 Miriam D Post  12 Kristine Cooper  13 Francesmary Modugno  11 Nadine Hempel  14 Wayne Stallaert  15 Christopher J Bakkenist  7 Simone Sidoli  6 Kathryn E Wellen  10 Benjamin G Bitler  16 David T Long  5 Nathaniel W Snyder  17 Katherine M Aird  18  19
Affiliations
  • 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].
Abstract

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.

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