title: Linking Cancer Metabolism to DNA Repair and Accelerated Senescence.
abstract: Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites, and/or metabolic inhibitors by tracking resolution of double-strand breaks (DSB) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase each enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc's effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in nonhomologous end-joining DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance, and promote genomic instability.
  
  
  CONCLUSIONS
  By defining a pathway from deregulated metabolism to enhanced DNA damage response in cancer, these data provide a rationale for targeting downstream epigenetic effects of metabolic reprogramming to block cancer cell immortality and overcome resistance to genotoxic stress.
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois. Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Efimova
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois. Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois.
authors.forename: Satoe
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Chemistry, The University of Chicago, Chicago, Illinois.
authors.forename: Noumaan A
authors.initials: NA
authors.lastname: Shamsi
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois. Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois.
authors.forename: Ding
authors.initials: D
authors.lastname: Wu
authors.affiliation: Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Edwardine
authors.initials: E
authors.lastname: Labay
authors.affiliation: Department of Chemistry, The University of Chicago, Chicago, Illinois.
authors.forename: Olesya A
authors.initials: OA
authors.lastname: Ulanovskaya
authors.affiliation: Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Department of Chemistry, The University of Chicago, Chicago, Illinois.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kozmin
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois. Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois. skron@uchicago.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kron
mesh_terms: D000117:Acetylglucosamine / Q000494:pharmacology; D016922:Cellular Senescence; D004247:DNA / Q000528:radiation effects; D004260:DNA Repair; D044127:Epigenesis, Genetic; D042822:Genomic Instability; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D005973:Glutamine; D004247:DNA; D000117:Acetylglucosamine