A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+
Abstract Cytidine deaminase (CDA) deficiency causes pyrimidine pool disequilibrium. We previously reported that the excess cellular dC and dCTP resulting from CDA deficiency jeopardizes genome stability, decreasing basal poly(ADP-ribose) polymerase 1 (PARP-1) activity and increasing ultrafine anapha...
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2020
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oai:doaj.org-article:8ad15deee6144d6588f0ef029ab239f52021-12-02T18:51:51ZA decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+10.1038/s41598-020-70874-62045-2322https://doaj.org/article/8ad15deee6144d6588f0ef029ab239f52020-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-70874-6https://doaj.org/toc/2045-2322Abstract Cytidine deaminase (CDA) deficiency causes pyrimidine pool disequilibrium. We previously reported that the excess cellular dC and dCTP resulting from CDA deficiency jeopardizes genome stability, decreasing basal poly(ADP-ribose) polymerase 1 (PARP-1) activity and increasing ultrafine anaphase bridge (UFB) formation. Here, we investigated the mechanism underlying the decrease in PARP-1 activity in CDA-deficient cells. PARP-1 activity is dependent on intracellular NAD+ concentration. We therefore hypothesized that defects of the NAD+ salvage pathway might result in decreases in PARP-1 activity. We found that the inhibition or depletion of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage biosynthesis pathway, mimicked CDA deficiency, resulting in a decrease in basal PARP-1 activity, regardless of NAD+ levels. Furthermore, the expression of exogenous wild-type NAMPT fully restored basal PARP-1 activity and prevented the increase in UFB frequency in CDA-deficient cells. No such effect was observed with the catalytic mutant. Our findings demonstrate that (1) the inhibition of NAMPT activity in CDA-proficient cells lowers basal PARP-1 activity, and (2) the expression of exogenous wild-type NAMPT, but not of the catalytic mutant, fully restores basal PARP-1 activity in CDA-deficient cells; these results strongly suggest that basal PARP-1 activity in CDA-deficient cells decreases due to a reduction of NAMPT activity.Sandra Cunha SilveiraGéraldine Buhagiar-LabarchèdeRosine Onclercq-DelicSimon GembleElias Bou SamraHamza MameriPatricia DuchambonChristelle MachonJérôme GuittonMounira Amor-GuéretNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-11 (2020) |
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Medicine R Science Q Sandra Cunha Silveira Géraldine Buhagiar-Labarchède Rosine Onclercq-Delic Simon Gemble Elias Bou Samra Hamza Mameri Patricia Duchambon Christelle Machon Jérôme Guitton Mounira Amor-Guéret A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+ |
| description |
Abstract Cytidine deaminase (CDA) deficiency causes pyrimidine pool disequilibrium. We previously reported that the excess cellular dC and dCTP resulting from CDA deficiency jeopardizes genome stability, decreasing basal poly(ADP-ribose) polymerase 1 (PARP-1) activity and increasing ultrafine anaphase bridge (UFB) formation. Here, we investigated the mechanism underlying the decrease in PARP-1 activity in CDA-deficient cells. PARP-1 activity is dependent on intracellular NAD+ concentration. We therefore hypothesized that defects of the NAD+ salvage pathway might result in decreases in PARP-1 activity. We found that the inhibition or depletion of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage biosynthesis pathway, mimicked CDA deficiency, resulting in a decrease in basal PARP-1 activity, regardless of NAD+ levels. Furthermore, the expression of exogenous wild-type NAMPT fully restored basal PARP-1 activity and prevented the increase in UFB frequency in CDA-deficient cells. No such effect was observed with the catalytic mutant. Our findings demonstrate that (1) the inhibition of NAMPT activity in CDA-proficient cells lowers basal PARP-1 activity, and (2) the expression of exogenous wild-type NAMPT, but not of the catalytic mutant, fully restores basal PARP-1 activity in CDA-deficient cells; these results strongly suggest that basal PARP-1 activity in CDA-deficient cells decreases due to a reduction of NAMPT activity. |
| format |
article |
| author |
Sandra Cunha Silveira Géraldine Buhagiar-Labarchède Rosine Onclercq-Delic Simon Gemble Elias Bou Samra Hamza Mameri Patricia Duchambon Christelle Machon Jérôme Guitton Mounira Amor-Guéret |
| author_facet |
Sandra Cunha Silveira Géraldine Buhagiar-Labarchède Rosine Onclercq-Delic Simon Gemble Elias Bou Samra Hamza Mameri Patricia Duchambon Christelle Machon Jérôme Guitton Mounira Amor-Guéret |
| author_sort |
Sandra Cunha Silveira |
| title |
A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+ |
| title_short |
A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+ |
| title_full |
A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+ |
| title_fullStr |
A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+ |
| title_full_unstemmed |
A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD+ |
| title_sort |
decrease in nampt activity impairs basal parp-1 activity in cytidine deaminase deficient-cells, independently of nad+ |
| publisher |
Nature Portfolio |
| publishDate |
2020 |
| url |
https://doaj.org/article/8ad15deee6144d6588f0ef029ab239f5 |
| work_keys_str_mv |
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