{"doi":"10.1101/2024.02.06.578742","title":"αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":484807,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":867712,"name":"Zhentai Huang","orcid":"0000-0002-8102-464X","position":1,"is_corresponding":false},{"id":557914,"name":"Raquel Buj","orcid":"0000-0002-8355-6666","position":2,"is_corresponding":false},{"id":1167877,"name":"Amandine Amalric","orcid":"0000-0002-2856-1446","position":3,"is_corresponding":false},{"id":299612,"name":"Hui Wang","orcid":"0000-0002-2454-3814","position":4,"is_corresponding":false},{"id":653684,"name":"Naveen Kumar Tangudu","orcid":"0000-0001-9153-5825","position":5,"is_corresponding":false},{"id":555568,"name":"Aidan R. 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Dahl","orcid":"0000-0001-6506-9103","position":14,"is_corresponding":false},{"id":240809,"name":"Nadine Hempel","orcid":"0000-0002-5574-8783","position":15,"is_corresponding":false},{"id":652998,"name":"Wayne Stallaert","orcid":"0000-0001-8064-6503","position":16,"is_corresponding":false},{"id":247704,"name":"Simone Sidoli","orcid":"0000-0001-9073-6641","position":17,"is_corresponding":false},{"id":246398,"name":"Benjamin G. Bitler","orcid":"0000-0002-5809-5271","position":18,"is_corresponding":false},{"id":733917,"name":"David T. Long","orcid":"0000-0001-9232-0316","position":19,"is_corresponding":false},{"id":237765,"name":"Nathaniel W. Snyder","orcid":"0000-0001-5643-8747","position":20,"is_corresponding":false},{"id":314761,"name":"Katherine M. 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