αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

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. We identified that depletion of KG sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. KG is required for the activity of KG-dependent dioxygenases (KGDDs), and prior work has shown that changes in KGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 KGDDs, 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, KG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation. The increase in histone acetylation via the 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 KG affects histone acetylation and provides a mechanism of HR-proficiency via carnitine synthesis. Moreover, these data provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Ovarian Fibroblast, Epithelial Ovarian Cancer Cell

SUBMITTER: Simone Sidoli  

LAB HEAD: Simone Sidoli

PROVIDER: PXD060690 | Pride | 2026-03-30

REPOSITORIES: Pride