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

Fouquerel, E and Goellner, EM and Yu, Z and Gagné, JP and de Moura, MB and Feinstein, T and Wheeler, D and Redpath, P and Li, J and Romero, G and Migaud, M and Van Houten, B and Poirier, GG and Sobol, RW (2014) ARTD1/PARP1 negatively regulates glycolysis by inhibiting hexokinase 1 independent of NAD<sup>+</sup> depletion. Cell Reports, 8 (6). 1819 - 1831.

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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.


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Fouquerel, E
Goellner, EM
Yu, Z
Gagné, JP
de Moura, MB
Feinstein, T
Wheeler, D
Redpath, P
Li, J
Romero, Gggr@pitt.eduGGR
Migaud, M
Van Houten, Bbev15@pitt.eduBEV15
Poirier, GG
Sobol, RWrws9@pitt.eduRWS9
Centers: Other Centers, Institutes, Offices, or Units > Hillman Cancer Center
Date: 25 September 2014
Date Type: Publication
Journal or Publication Title: Cell Reports
Volume: 8
Number: 6
Page Range: 1819 - 1831
DOI or Unique Handle: 10.1016/j.celrep.2014.08.036
Schools and Programs: Graduate School of Public Health > Human Genetics
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Date Deposited: 22 May 2015 21:51
Last Modified: 12 Oct 2021 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/24721

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