Investigator:  Deyu Li, University of Rhode Island

Mentor:  Bingfang Yan, University of Rhode Island

Scientific Theme:  Cancer

Abstract:  Nuclear and mitochondrial DNA is damaged by radiation, by organic and inorganic chemical agents, and by the misdirected activity of enzymes. DNA adducts arising from nucleic acid damage may cause the development and acceleration of cancer. To avoid the undesirable effects of DNA adducts, living organisms have developed a host of DNA repair systems that act as defenses against the threats that these adducts pose to cellular welfare.Oxidative DNA repair mediated by the AlkB family demethylases has been one of the most exciting and fast growing research areas during the past decade. So far, nine human homologs of the E. coli AlkB protein have been identified (ABH1-8 and FTO). In the event of oxidative dealkylation, the AlkB family proteins use an α-ketoglutarate (αKG)/Fe(II)-dependent mechanism to oxidize the aberrant alkyl groups, ultimately restoring the undamaged DNA bases. This oxidation mechanism is shared by more than sixty human enzymes within the nonheme iron-containing protein family, including the JmjC histone demethylasesand TET family m5C hydroxylases.Recently, pioneering studies demonstrated that the Jmjc and TET family of enzymes can be inhibited by 2-hydroxyglutarate (2HG) via competitive binding to the Fe(II) center and replacing αKG, thus leading to epigenetic changes in eukaryotic cells. 2HG, an oncometabolite closely related to the tricarboxylic cycle (TCA) cycle, is generated by mutated isocitrate dehydrogenase 1 (IDH1) and IDH2. These enzymes normally catalyze the interconversion between isocitrate and αKG in the TCA cycle. Cancer-associated IDH mutations alter these enzymes such that the natural αKG substrate is diminished, while the structurally similar metabolite 2HG accumulates to high levels (up to millimolar concentration) within cells. These observations provide a link between alterations in cellular energy metabolism and oncogenesis. Thisproject is directed toward understanding oncometabolite 2HG’s inhibitory effect on the αKG-dependent AlkB proteins.We shall use chemical, spectroscopic, and genetic tools to investigate biological processes of DNA repair and metabolism, and develop therapies for cancer and other diseases.

Human Health Relevance:  DNA damage is now recognized as a major factor in the etiology of many types of cancer. The proposed research will open new understanding of the relationship between DNA damage repair enzymes and cellular energy metabolism. The inhibitory effect of oncometabolites on DNA repair contributes strongly to the process leading to cancer.