PXD060690-1

PXD060690 is an original dataset announced via ProteomeXchange.

Title	αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation
Description	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.
HostingRepository	PRIDE
AnnounceDate	2026-03-31
AnnouncementXML	Submission_2026-03-31_09:58:18.599.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simone Sidoli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-11 09:56:07	ID requested
⏵ 1	2026-03-31 09:58:19	announced

Dataset with its publication pending

submitter keyword: ovarian cancer,Epigenetics, DNA damaging agents, isocitrate dehydrogenase, glutamine, acetylcarnitine, TMLHE, cyclin E

Simone Sidoli
contact affiliation	Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, United States
contact email	simone.sidoli@einsteinmed.edu
lab head
Simone Sidoli
contact affiliation	Albert Einstein College of Medicine
contact email	simone.sidoli@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060690
     1. Label: PRIDE project
     2. Name: αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation