Abstract SY21-02: Oncometabolites suppress homologous recombination DNA repair by inhibition of chromatin remodeling at the DNA double-strand break

Abstract

Abstract Elevated levels of the metabolites, 2-hydroxyglutarate (2HG), fumarate, and succinate, can occur in human malignancies due to somatic mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes or germline mutations in fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes, respectively. Mutations in IDH1 and IDH2 are found in a large number of human malignancies, most notably gliomas and acute myelogenous leukemias, along with cholangiocarcinomas, chondrosarcomas, and melanomas. Inherited mutations in FH and SDH, are linked to the familial cancer predisposition syndromes, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Hereditary Paraganglioma and Pheochromocytoma (SDH PGL/PCC), respectively. These structurally related metabolites inhibit α-ketoglutarate-dependent enzymes, including dioxygenases that modify chromatin. We have shown that they consequently suppress the pathway of homology-dependent DNA repair (HDR), conferring an exquisite sensitivity to PARP inhibitors that is currently being tested in clinical trials. In this presentation, we will discuss our recent work elucidating the mechanistic basis for this suppression of DNA repair. Rather than acting indirectly through epigenetic regulation of gene expression, we find that these metabolites act directly by inhibiting HDR factor recruitment to DNA double-strand breaks (DSBs). The metabolites inhibit the lysine demethylases, KDM4A/B, causing aberrant hypermethylation of H3K9 and disrupting signaling at the break, thereby delaying the stepwise recruitment of key HDR factors. These results define a novel mechanism of decreased DNA repair in oncometabolite producing human tumors and may provide the basis for the rational design of novel therapeutic strategies for these malignancies. Citation Format: Parker S. Sulkowski, Sebstian Oeck, Jing Li, Brian Shuch, Megan C. King, Ranjit S. Bindra, Peter M. Glazer. Oncometabolites suppress homologous recombination DNA repair by inhibition of chromatin remodeling at the DNA double-strand break [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY21-02.