DNA Repair: Novel pathways that regulate the DNA damage response.

Recently, in collaborative work with the Bindra lab, we discovered that the oncometabolite, 2-hydroxyglutarate, generated by neomorphic IDH mutations in gliomas and other malignancies suppresses homologous recombination and confers PARP inhibitor sensitivity, identifying a new approach to treat these malignancies (Sulkowski, Science Translational Medicine, 2017). Similarly, we found that elevated level of the Krebs cycle intermediates, fumarate and succinate, associated with the hereditary cancer syndromes, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Succinate Dehydrogenase-related Hereditary Paraganglioma and Pheochromocytoma (SDH PGL/PCC), also suppress the homologous recombination pathway, rendering these tumors vulnerable to synthetic lethal targeting with PARP inhibitors, pointing to a new therapeutic approach for advanced HLRCC and SDH PGL/PCC, both incurable when metastatic (Sulkowski, Nature Genetics, 2018). The use of PARP inhibitors in these malignancies is currently being tested in several clinical trials directly based on our work. Mechanistically, we determined that oncometabolites suppress homology dependent repair (HDR) by inhibiting the histone lysine demethylase, KDM4B. This causes aberrant hypermethylation of H3K9 across the genome and thereby disrupts the normal temporal and spatial pattern of HDR factor recruitment to sites of DNA DSBs (Sulkowski, Nature, 2020). We also recently characterized a novel pathway by which mitochondrial DNA damage mediates signaling to upregulate nuclear DNA repair (Wu, Nature Metabolism, 2019).