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

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85 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)1819-1831
Number of pages13
JournalCell Reports
Volume8
Issue number6
Early online date15 Sep 2014
DOIs
Publication statusPublished - 25 Sep 2014

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