ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ depletion

Elise Fouquerel, Eva M. Goellner, Zhongxun Yu, Jean Philippe Gagné, Michelle Barbi de Moura, Tim Feinstein, David Wheeler, Philip Redpath, Jianfeng Li, Guillermo Romero, Marie Migaud, Bennett Van Houten, Guy G. Poirier, Robert W. Sobol

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


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.

Original languageEnglish
Pages (from-to)1819-1831
Number of pages13
JournalCell Reports
Issue number6
StatePublished - Sep 25 2014

Bibliographical note

Funding Information:
This work was supported by grants from NIH (CA148629, GM087798, ES019498, ES021116, GM099213, and CA148629-04S1) to R.W.S., from the Canadian Institutes of Health Research (MOP-178013, MOP-209278) to G.G.P., and from PA CURE to B.V.H. Support for the synthetic chemistry conducted by P.R. was provided by the John King Laboratory Funds. Support was also provided by the University of Pittsburgh Department of Pharmacology & Chemical Biology through a Pharmacology Fellowship to E.M.G. G.G.P. holds a Tier1 Canada Chair in Proteomics. B.V.H. holds the Richard M. Cyert Chair as Professor of Molecular Oncology. Support for the UPCI Lentiviral (Vector Core) Facility and the UPCI Cell and Tissue Imaging Facility was provided in part by the Cancer Center Support Grant from the NIH (P30CA047904). RWS is a scientific consultant for Trevigen, Inc.

Publisher Copyright:
© 2014 The Authors.

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)


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