αKG-mediated carnitine synthesis drives DNA repair via histone acetylation

• 成果类型: Article
• 署名作者: Uboveja, Apoorva; Yang, Baixue; Buj, Raquel; Amalric, Amandine; Wang, Hui; Tangudu, Naveen Kumar; Cole, Aidan R.; Disharoon, Julie A.; Fang, Richard S.; Levasseur, Evan; Naruse, Miho; Huang, Zhentai; Megill, Emily; Kantner, Daniel S.; Chatoff, Adam; Ahmad, Hafsah; Marcinkiewicz, Mariola M.; Graff, Sarah; De Pieri, Ellen; Huacachino, Andrea Andress; Vendetti, Frank P.; Danielson, Jeff; Dahl, Erika S.; Pennise, Jennifer L.; Elishaev, Esther; Jaccard, Alison; Borho, Lauren; Post, Miriam D.; Cooper, Kristine; Modugno, Francesmary; Hempel, Nadine; Stallaert, Wayne; Bakkenist, Christopher J.; Sidoli, Simone; Wellen, Kathryn E.; Bitler, Benjamin G.; Long, David T.; Snyder, Nathaniel W.; Aird, Katherine M.
• 署名单位: The Wistar Institute; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Tsinghua University; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University; Medical University of South Carolina; Montefiore Medical Center; Yeshiva University; Albert Einstein College of Medicine; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Pennsylvania; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Magee-Womens Research Institute; University of Colorado System; University of Colorado Anschutz; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Colorado System; University of Colorado Anschutz
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-026-10584-7
• 发表日期: 2026-07-16
• 关键词: analysis reveals; ACYL-COENZYME; cancer; MILDRONATE; transport; promotes; cells

摘要

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 alpha-ketoglutarate (alpha KG) sensitizes HR-proficient cells to DNA-damaging agents by metabolic regulation of histone acetylation. alpha KG is required for the activity of alpha KG-dependent dioxygenases2 (alpha KGDDs), and previous work has focused almost exclusively on the demethylase functions of alpha KGDD. Using a targeted CRISPR knockout library consisting of 64 alpha KGDDs, 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, alpha KG-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 alpha KG-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 alpha KG 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.