αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

Apoorva Uboveja, Zhentai Huang, Raquel Buj, Amandine Amalric, Hui Wang, Naveen Kumar Tangudu, Aidan R Cole, Emily Megill, Daniel Kantner, Adam Chatoff, Hafsah Ahmad, Mariola M Marcinkiewicz, Julie A Disharoon, Sarah Graff, Erika S Dahl, Nadine Hempel, Wayne Stallaert, Simone Sidoli, Benjamin G Bitler, David T LongNathaniel W Snyder, Katherine M Aird

Research output: Working paperPreprint

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.

Original languageEnglish
DOIs
StatePublished - Feb 11 2024

Publication series

NamebioRxiv

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