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.
|Number of pages||13|
|State||Published - Sep 25 2014|
Bibliographical noteFunding 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.
© 2014 The Authors.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)