Peer-reviewedCC BY-NC-NDNature
αKG-mediated carnitine synthesis drives DNA repair via histone acetylation
19 affiliations
- 1Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- 2Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA
- 3Tsinghua University, Beijing, China
- 4Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- 5Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- 6Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
- 7Department of Radiation Oncology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- 8Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA
- 9Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- 10Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA
- 11Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
- 12Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- 13Biostatistics Facility, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
- 14Department of Medicine, Division of Hematology/Oncology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- 15Department of Computational & Systems Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- 16Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- 17Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. [email protected]
- 18Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected]
- 19Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA. [email protected]
Abstract
Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-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 dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. 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 proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis and provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.
Related
- Histone lactylation in fibroblast-like synoviocytes drives CXCL1-mediated immune cell recruitment in rheumatoid arthritis
- Histone Acetylation in Bone Remodeling: Metabolic Regulation, Lineage-Specific Chromatin Programs, and Therapeutic Implications
- Nuclear acetyl-CoA production by acetyl-CoA synthetase enables dynamic histone acetylation and gene expression in Plasmodium falciparum
- Influence of Histone Acetylation on Chromatin 3D Organization in Drosophila S2 Cells.
- Intranuclear localisation of KLF3‐AS1 under the balance of histone acetylation and methylation in BMSCs ameliorates cerebral ischaemia‒reperfusion injury by preserving microglial mitochondrial function and inhibiting inflammatory polarisation
BibTeX
@article{uboveja2026αkgmediated,
title = {{αKG-mediated carnitine synthesis drives DNA repair via histone acetylation}},
author = {Apoorva Uboveja and Baixue Yang and Raquel Buj and Amandine Amalric and Hui Wang and Naveen Kumar Tangudu and Aidan R. Cole and Julie A. Disharoon and Richard S. Fang and Evan Levasseur and Miho Naruse and Zhentai Huang and Emily Megill and Daniel S. Kantner and Adam G. Chatoff and Hafsah Ahmad and Mariola M. Marcinkiewicz and Sarah Graff and Ellen De Pieri and Andrea Andress Huacachino and Frank P. Vendetti and Jeff Danielson and Erika S. Dahl and Jennifer L Pennise and Esther Elishaev and Alison Jaccard and Lauren Borho and Miriam D. Post and Kristine Cooper and Francesmary Modugno and Nadine Hempel and Wayne Stallaert and Christopher J. Bakkenist and Simone Sidoli and Kathryn E. Wellen and Benjamin Guy Bitler and David T. Long and Nathaniel W. Snyder and Katherine M. Aird},
journal = {Nature},
year = {2026},
month = may,
doi = {10.1038/s41586-026-10584-7},
url = {https://doi.org/10.1038/s41586-026-10584-7},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - αKG-mediated carnitine synthesis drives DNA repair via histone acetylation
AU - Apoorva Uboveja
AU - Baixue Yang
AU - Raquel Buj
AU - Amandine Amalric
AU - Hui Wang
AU - Naveen Kumar Tangudu
AU - Aidan R. Cole
AU - Julie A. Disharoon
AU - Richard S. Fang
AU - Evan Levasseur
AU - Miho Naruse
AU - Zhentai Huang
AU - Emily Megill
AU - Daniel S. Kantner
AU - Adam G. Chatoff
AU - Hafsah Ahmad
AU - Mariola M. Marcinkiewicz
AU - Sarah Graff
AU - Ellen De Pieri
AU - Andrea Andress Huacachino
AU - Frank P. Vendetti
AU - Jeff Danielson
AU - Erika S. Dahl
AU - Jennifer L Pennise
AU - Esther Elishaev
AU - Alison Jaccard
AU - Lauren Borho
AU - Miriam D. Post
AU - Kristine Cooper
AU - Francesmary Modugno
AU - Nadine Hempel
AU - Wayne Stallaert
AU - Christopher J. Bakkenist
AU - Simone Sidoli
AU - Kathryn E. Wellen
AU - Benjamin Guy Bitler
AU - David T. Long
AU - Nathaniel W. Snyder
AU - Katherine M. Aird
PY - 2026
DA - 2026/05/27
JO - Nature
DO - 10.1038/s41586-026-10584-7
UR - https://doi.org/10.1038/s41586-026-10584-7
AB - Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-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 dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. 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 proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis and provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.
SN - 0028-0836
SN - 1476-4687
ER -