Carnitine Synthesis Links αKG to Histone Acetylation and HR-Mediated DNA Repair

Genome stability depends on efficient DNA repair, yet cancer cells frequently exploit dysregulation of repair pathways, such as homologous recombination (HR), to survive therapy. While HR-deficient tumors respond well to DNA-damaging agents, HR-proficient tumors are largely resistant, and the basis for this proficiency remains poorly understood. Histone post-translational modifications are key regulators of DNA repair and are sensitive to metabolic inputs, particularly α-ketoglutarate (αKG), which regulates chromatin state through αKG-dependent dioxygenases (αKGDD). Although previous studies have primarily focused on demethylases, Uboveja and colleagues uncover a broader role for αKG in driving a histone acetylation program essential for HR proficiency and chemotherapy resistance. Building on their prior observation that the αKG-producing enzyme IDH1 is elevated in high-grade serous ovarian cancer with high CCNE1 expression, the authors show that CCNE1 overexpression, which leads to HR proficiency, increases αKG abundance and that depleting αKG through multiple avenues, including IDH1 inhibitors, sensitizes CCNE1-driven cells to DNA-damaging agents in an αKGDD-dependent manner. A CRISPR knockout screen targeting all αKGDDs identified TMLHE, a carnitine biosynthesis enzyme, as the key mediator: Loss of TMLHE sensitized cells to DNA damage, which could be rescued by L-carnitine but not αKG, placing TMLHE function downstream of αKG. αKG depletion reduced L-carnitine abundance in vitro and in vivo, with isotope tracing analysis confirming that de novo carnitine synthesis through TMLHE was αKG-dependent. Acetylcarnitine served as a precursor for nuclear acetyl-CoA, and αKG depletion suppressed global H3 and H4 acetylation, specifically H3K23ac, H4K8ac, and H4K12ac. Functionally, αKG depletion increased DNA damage foci and reduced RAD51 foci in CCNE1-overexpressing cells, indicating that the αKG–carnitine axis supports HR through histone acetylation at double-strand breaks. In patient samples, CCNE1 and TMLHE expression correlated with histone acetylation, and high TMLHE expression at recurrence predicted worse progression-free survival. In a CCNE1-driven mouse model, mildronate, a carnitine synthesis inhibitor, combined with cisplatin reduced tumor burden by over 30% without systemic toxicity. These findings reveal an unappreciated function of αKG beyond demethylation, providing new insights into the metabolic mechanisms that sustain HR proficiency and chemotherapy resistance.Uboveja A, Yang B, Buj R, Amalric A, Wang H, Tangudu NK, et al. αKG-mediated carnitine synthesis drives DNA repair via histone acetylation. Nature 2026 May 27 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.