αKG-mediated carnitine synthesis drives DNA repair via histone acetylation

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. The metabolite αKG promotes carnitine synthesis and increases site-specific histone acetylation, thereby promoting homologous recombination-mediated DNA repair, which has potential implications for chemoresistant cancers.

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Journal
Nature
Published
2026-05-27
DOI
https://doi.org/10.1038/s41586-026-10584-7
Primary Topic
DNA Repair Mechanisms
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article
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article

αKG-mediated carnitine synthesis drives DNA repair via histone acetylation

Naveen Kumar Tangudu, Amandine Amalric, Benjamin G. Bitler, Daniel S. Kantner et al.
Nature
DNA Repair Mechanisms
article

αKG-mediated carnitine synthesis drives DNA repair via histone acetylation

Naveen Kumar Tangudu, Amandine Amalric, Benjamin G. Bitler, Daniel S. Kantner, Jeff Danielson, Wayne Stallaert, Frank P. Vendetti, Richard Fang, Mariola M. Marcinkiewicz, Nadine Hempel, David T. Long, Erika S. Dahl, Apoorva Uboveja, Katherine M. Aird, Zhentai Huang, Raquel Buj, Nathaniel W. Snyder, Francesmary Modugno, Alison Jaccard, Julie A. Disharoon, Hafsah Ahmad, Ellen De Pieri, Kathryn E. Wellen, Andrea Andress Huacachino, K M Cooper, Lauren Borho, Evan Levasseur, Jennifer L. Pennise, Miriam D. Post, Emily Megill, Adam Chatoff, Christopher J. Bakkenist, Hui Wang, Esther Elishaev, Miho Naruse, Aidan R. Cole, Simone Sidoli, Sarah Graff, Baixue Yang
article en

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. The metabolite αKG promotes carnitine synthesis and increases site-specific histone acetylation, thereby promoting homologous recombination-mediated DNA repair, which has potential implications for chemoresistant cancers.

Nature
The Wistar Institute (US), Albert Einstein College of Medicine (US), Medical University of South Carolina (US), University of Pittsburgh (US), MUSC Hollings Cancer Center (US), Magee-Womens Research Institute (US), UPMC Hillman Cancer Center (US), University of Colorado Anschutz Medical Campus (US), University of Pennsylvania (US), Penn State Milton S. Hershey Medical Center (US), Temple University (US), Tsinghua University (CN)
Good health and well-being
Openalex Percentile: Top 10%
DNA Repair Mechanisms
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