Oncometabolites suppress DNA repair by disrupting local chromatin signalling

Abstract

Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer 1 . 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.

Oncometabolites and the response to radiotherapy

“…In line with this observations, recent studies further associated the function of KDMs to regulation of HRR and radioresistance of lung cancer patients [24,115,130]. Moreover, a recently published study by Sulkowski and coworkers has dissected some mechanistic aspects of the link between 2-HG and DSB repair on the level of KDM4B mediated H3K9me3 histone 3 lysine 9 trimethylation (H3K9me3) near DNA breaks [129]. In more detail, 2-HG mediated KDM4B inhibition resulted in an increase of H3K9me3 at loci surrounding DNA breaks.…”

“…In more detail, 2-HG mediated KDM4B inhibition resulted in an increase of H3K9me3 at loci surrounding DNA breaks. The alteration of the histone marks interfered with proper recruitment of TIP60 and ATM, thereby reducing end resection and impairing downstream DNA repair [129]. This study emphasizes the pivotal role of 2-HG-mediated suppression of HRR and provides an excellent explanation for the relationship between oncometabolites, the DNA damage response and DSB repair [129].…”

A Comprehensive Proteomics Analysis of the JC Virus (JCV) Large and Small Tumor Antigen Interacting Proteins: Large T Primarily Targets the Host Protein Complexes with V-ATPase and Ubiquitin Ligase Activities While Small t Mostly Associates with Those Having Phosphatase and Chromatin-Remodeling Functions

“…It was surprising to discover that the inherited or somatic mutations in SDH genes could lead to different cancers such as paraganglioma or phaeochromocytoma catecholamine-producing neuroendocrine tumors [ 136 , 137 , 138 , 139 ], gastrointestinal tumors (GIST) [ 140 ]. A very recent work indicated that SDH mutations may lead to the defects in homologous DNA repair [ 141 ] and disruption in chromatin signaling [ 142 ]. Collectively, these studies implicated that SDH plays a role in tumor suppression as well as in chromatin modeling.…”

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

“…KDM4B inhibition leads to basal hypermethylation of H3K9, masking a local spike in trimethylation at DSB sites, which impairs recruitment of repair factors, such as TIP60 and ATM. End-resection and recruitment of downstream repair factors is consequently impaired [181]. Thus, the epigenetic changes induced by 2HG generate an HR defect, which confers a "BRCAness" phenotype, hence sensitizing such tumors to PARP inhibitors.…”