title: ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ depletion.
abstract: ARTD1 (PARP1) is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose) (PAR) in response to strand breaks, and it plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD(+) depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD(+) depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD(+) depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1) as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Fouquerel
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Goellner
authors.affiliation: University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA; School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.
authors.forename: Zhongxun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Centre de recherche du CHU de Québec, Université Laval, Faculté de Médecine, Québec, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Gagné
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Barbi de Moura
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Feinstein
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wheeler
authors.affiliation: School of Pharmacy, Queen's University, Belfast BT9 7BL, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Redpath
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Romero
authors.affiliation: School of Pharmacy, Queen's University, Belfast BT9 7BL, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Migaud
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.affiliation: Centre de recherche du CHU de Québec, Université Laval, Faculté de Médecine, Québec, Canada.
authors.forename: Guy G
authors.initials: GG
authors.lastname: Poirier
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA. Electronic address: rws9@pitt.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004734:Energy Metabolism; D006019:Glycolysis / Q000502:physiology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006593:Hexokinase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D040901:Proteomics; D016415:Sequence Alignment
chemical_list: D009243:NAD; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D006593:Hexokinase; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase