2. Academic Validation
  3. αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

  • bioRxiv. 2024 Feb 11:2024.02.06.578742. doi: 10.1101/2024.02.06.578742.
Apoorva Uboveja 1,  Zhentai Huang 1,  Raquel Buj 1,  Amandine Amalric 1 2,  Hui Wang 1,  Naveen Kumar Tangudu 1,  Aidan R Cole 1,  Emily Megill 2,  Daniel Kantner 2,  Adam Chatoff 2,  Hafsah Ahmad 2,  Mariola M Marcinkiewicz 2,  Julie A Disharoon 3,  Sarah Graff 4,  Erika S Dahl 5,  Nadine Hempel 6,  Wayne Stallaert 7,  Simone Sidoli 4,  Benjamin G Bitler 8,  David T Long 3,  Nathaniel W Snyder 2,  Katherine M Aird 1
Affiliations

Affiliations

  • 1 Department of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • 2 Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.
  • 3 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina.
  • 4 Department of Biochemistry, Albert Einstein College of Medicine, The Bronx, NY.
  • 5 Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania.
  • 6 Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, PA, USA.
  • 7 Department of Computational & Systems Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • 8 Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Denver, Colorado.
PMID: 38370789 DOI: 10.1101/2024.02.06.578742
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.

Keywords

DNA damaging agents; Epigenetics; alpha-ketoglutarate; cyclin E; histone acetylation; homologous recombination; isocitrate dehydrogenase; ovarian cancer.

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