title: Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents.
abstract: Chemotherapy of a combination of DNA alkylating agents, procarbazine and lomustine (CCNU), and a microtubule poison, vincristine, offers a significant benefit to a subset of glioma patients. The benefit of this regimen, known as PCV, was recently linked to IDH mutation that occurs frequently in glioma and produces D-2-hydroxyglutarate (D-2-HG), a competitive inhibitor of α-ketoglutarate (α-KG). We report here that D-2-HG inhibits the α-KG-dependent alkB homolog (ALKBH) DNA repair enzymes. Cells expressing mutant IDH display reduced repair kinetics, accumulate more DNA damages, and are sensitized to alkylating agents. The observed sensitization to alkylating agents requires the catalytic activity of mutant IDH to produce D-2-HG and can be reversed by the deletion of mutant IDH allele or overexpression of ALKBH2 or AKLBH3. Our results suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents may merit exploration for treating IDH-mutated cancer patients.
authors.affiliation: Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Ma
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China; Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China. Electronic address: yedan@fudan.edu.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000071499:AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; D000477:Alkylating Agents / Q000633:toxicity*; D002066:Busulfan / Q000633:toxicity; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D005977:Glutarates; D007656:Ketoglutaric Acids; D034741:RNA, Small Interfering; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C486439:ALKBH3 protein, human; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; C486440:ALKBH2 protein, human; D000071499:AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; D045643:DNA Repair Enzymes; D002066:Busulfan