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A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of
Sandra Cunha Silveira1,2,3, Géraldine Buhagiar-Labarchède1,2,3, Rosine Onclercq-Delic1,2,3
1Institut Curie, UMR 3348, PSL Research University, 91405, Orsay, France.
Scientific Reports
|August 19, 2020
Summary
Cytidine deaminase (CDA) deficiency reduces poly(ADP-ribose) polymerase 1 (PARP-1) activity by impairing nicotinamide phosphoribosyltransferase (NAMPT). Restoring NAMPT function corrects PARP-1 activity and genome stability in CDA-deficient cells.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Cytidine deaminase (CDA) deficiency leads to pyrimidine pool imbalance.
- This imbalance causes genome instability, reduced poly(ADP-ribose) polymerase 1 (PARP-1) activity, and increased ultrafine anaphase bridges (UFBs).
Purpose of the Study:
- To investigate the mechanism by which CDA deficiency decreases PARP-1 activity.
- To determine the role of the NAD+ salvage pathway, specifically nicotinamide phosphoribosyltransferase (NAMPT), in this process.
Main Methods:
- Inhibition or depletion of NAMPT in CDA-proficient cells.
- Expression of wild-type and catalytic mutant NAMPT in CDA-deficient cells.
- Measurement of PARP-1 activity and UFB frequency.
Main Results:
- NAMPT inhibition mimicked CDA deficiency, decreasing PARP-1 activity independently of NAD+ levels.
- Exogenous wild-type NAMPT restored PARP-1 activity and reduced UFBs in CDA-deficient cells.
- A catalytic mutant of NAMPT did not restore PARP-1 activity.
Conclusions:
- CDA deficiency decreases basal PARP-1 activity due to reduced NAMPT activity.
- NAMPT is crucial for maintaining PARP-1 activity and genome stability in the context of CDA deficiency.
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