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

doi:10.1016/j.celrep.2014.08.036

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 journal › Article › peer-review

144 Scopus citations

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 language	English
Pages (from-to)	1819-1831
Number of pages	13
Journal	Cell Reports
Volume	8
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2014.08.036
State	Published - 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)

Access to Document

10.1016/j.celrep.2014.08.036

Cite this

Fouquerel, E., Goellner, E. M., Yu, Z., Gagné, J. P., de Moura, M. B., Feinstein, T., Wheeler, D., Redpath, P., Li, J., Romero, G., Migaud, M., Van Houten, B., Poirier, G. G., & Sobol, R. W. (2014). ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD⁺ depletion. Cell Reports, 8(6), 1819-1831. https://doi.org/10.1016/j.celrep.2014.08.036

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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.",

author = "Elise Fouquerel and Goellner, {Eva M.} and Zhongxun Yu and Gagn{\'e}, {Jean Philippe} and {de Moura}, {Michelle Barbi} and Tim Feinstein and David Wheeler and Philip Redpath and Jianfeng Li and Guillermo Romero and Marie Migaud and {Van Houten}, Bennett and Poirier, {Guy G.} and Sobol, {Robert W.}",

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: {\textcopyright} 2014 The Authors.",

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T1 - ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD+ depletion

AU - Fouquerel, Elise

AU - Goellner, Eva M.

AU - Yu, Zhongxun

AU - Gagné, Jean Philippe

AU - de Moura, Michelle Barbi

AU - Feinstein, Tim

AU - Wheeler, David

AU - Redpath, Philip

AU - Li, Jianfeng

AU - Romero, Guillermo

AU - Migaud, Marie

AU - Van Houten, Bennett

AU - Poirier, Guy G.

AU - Sobol, Robert W.

N1 - 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.

PY - 2014/9/25

Y1 - 2014/9/25

N2 - 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.

AB - 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.

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