Oncometabolites suppress DNA repair by disrupting local chromatin signaling

Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer1. Elevated levels of the metabolites, 2-hydroxyglutarate (2HG), succinate, and fumarate, occur in human malignancies due to somatic mutations in the isocitrate dehydrogenase-1/2 (IDH1/2) genes or germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes, respectively(2–4). Recent work has made an unexpected connection between these metabolites and DNA repair by showing that they suppress the pathway of homology-dependent repair (HDR)(5,6) and confer an exquisite sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors that is being tested in clinical trials. However, the mechanism by which these oncometabolites inhibit HDR remains poorly understood. Here we elucidate the pathway by which these metabolites disrupt DNA repair. We show that oncometabolite-induced inhibition of the lysine demethylase KDM4B results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of HDR. Consequently, recruitment of Tip60 and ATM, two key proximal HDR factors, is significantly impaired at DNA breaks, with reduced end-resection and diminished recruitment of downstream repair factors. These findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.